bims-axbals 2025-09-07 papers

bims-axbals

Biomed News

on Axonal biology and ALS

Issue of 2025–09–07
thirty-one papers selected by
TJ Krzystek

C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.
Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i3Neuronal Models of ALS/FTD Pathogenesis.
PolyQ-expansion of Ataxin-2 disrupts microtubule stability and impairs axon outgrowth.
Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.
TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.
C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules.
Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
Intracellular and Extracellular Vesicle miRNA Signatures in Human iPSC-Derived Neural Stem Cells and Floor Plate Progenitors.
De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation.
Restoration of Lysosomal Hydrolase Activities by LRRK2 Inhibition in GBA1- and LRRK2-Associated Parkinson's Disease Patient-Derived Cells.
Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.
Wnt7b Promotes Axon Differentiation and Extension by Regulating JNK-Mediated Cytoskeletal Dynamics.
Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models.
The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.
Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease.
Huntington's chorea: emerging fields in therapeutics (Review).
TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.
Loss of synaptic Munc13-1 underlies neurotransmission abnormalities in spinal muscular atrophy.
Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond.
Selectivity profiles and substrate recognition of Rab-phosphorylating kinases.
MCS Ultrastructural Analyses Using Electron Microscopy.
Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved TBM motif.
An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.
Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders.
Synaptic imbalance and increased inhibition impair motor function in SMA.
Ubiquitin-specific protease 7 promotes the growth and oncogenic potential of acute myeloid leukemia cells through the deubiquitination and upregulation of LRRK2.
Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics.
Mask protein keeps NF-κB precursor inactive by inducing a closed conformation and isolating it in biomolecular condensates.
The dual nature of neuroinflammation in networked brain.
Mitochondrial Quality Control.
Role of Netrin-1 dysregulation in early neuronal pathology of α-synuclein models of Parkinson's disease.

Glia. 2025 Sep 01.

C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC-Derived Microglia and Modulates Glial-Neuronal Crosstalk.

Marika Mearelli, Insa Hirschberg, Christin Weissleder, Carmela Giachino, María José Pérez, Malvina Dubroux, Francesca Provenzano, Mafalda Rizzuti, Linda Ottoboni, Udit Sheth, Tania F Gendron, Stefania Corti, Michela Deleidi.

  The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type-specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)-derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single-cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC-derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia-driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.

Keywords:   C9orf72 ; amyotrophic lateral sclerosis/frontotemporal dementia; glial‐neuronal communication; immune system; induced pluripotent stem cells; microglia

DOI:  https://doi.org/10.1002/glia.70080
Am J Physiol Cell Physiol. 2025 Aug 28.

Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i3Neuronal Models of ALS/FTD Pathogenesis.

Layla T Ghaffari, Emily A Welebob, Sarah E B Newton, Ashley V Boehringer, Kelly L Cyliax, Piera Pasinelli, Davide Trotti, Aaron R Haeusler.

  The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9orf72 (C9) gene is the most common cause of ALS and FTD. Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE iPSC-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization, or a blockade of K+ channels, followed by RNA sequencing, induces a temporally divergent activity-dependent transcriptome of C9-NRE cortical neurons compared to healthy controls. This study provides new insights into how neuronal activity influences the ALS/FTD-associated transcriptome, offering a dataset that enables further exploration of pathways necessary for conferring neuronal resilience or degeneration.

Keywords:  ALS/FTD; C9orf72; Neuronal activity; iPSC-dervied neurons; transcriptomics

DOI:  https://doi.org/10.1152/ajpcell.00238.2025
J Neurosci. 2025 Sep 04. pii: e0682252025. [Epub ahead of print]

PolyQ-expansion of Ataxin-2 disrupts microtubule stability and impairs axon outgrowth.

Sun K Kim, Vladimir I Gelfand.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by mislocalization and aggregation of proteins in motor neurons. Ataxin-2 (ATXN2), an RNA-binding protein harboring 22-polyglutamine (polyQ) repeats, is a risk factor for ALS, when its polyQ repeats are expanded to 27-33 repeats. However, the physiological function of ATXN2 beyond its role in RNA regulation, and how polyQ expansion in ATXN2 increases risk for ALS, remain unclear. We previously demonstrated that Drosophila Atx2 functions as a regulator of microtubule (MT) dynamics in motor neurons. Here, we uncover the molecular mechanism underlying Atx2-mediated MT regulation and how polyQ expansion disrupts its function, using a mixed-sex population of Drosophila as a model system. Specifically, we show that Atx2 requires its RNA-binding Lsm domain to regulate MTs. Notably, the LSM domains of human ATXN2 rescue MT phenotype in Drosophila, demonstrating an evolutionarily conserved role of ATXN2 in MT regulation. Importantly, we find that polyQ-expanded ATXN2 forms cytoplasmic aggregates and leads to excessive MT destabilization. Additionally, polyQ expansion severely impairs axon outgrowth. Finally, we identify Uncoordinated-76 (UNC-76/FEZ1) as a downstream effector of Atx2 in MT regulation and neuronal development.Significance Statement ALS is a progressive neurodegenerative disease with no effective treatment. Although polyglutamine (polyQ) expansion in the RNA-binding protein ATXN2 is a known risk factor for ALS, its mechanistic role in ALS pathogenesis has remained unclear. We demonstrate that ATXN2 regulates MT dynamics via its RNA-binding domain, and this role is evolutionarily conserved between Drosophila and humans. We further identify UNC-76/FEZ1 as a downstream effector of ATXN2 in regulating MT dynamics and neuronal development. Importantly, this study reveals how polyQ expansion in ATXN2 disrupts MT stability and axon growth, proposing a mechanism that may contribute to increased ALS risk.

DOI: https://doi.org/10.1523/JNEUROSCI.0682-25.2025
Acta Neuropathol Commun. 2025 Sep 02. 13(1): 188

Optineurin deficiency disrupts phosphorylated tau proteostasis and clusterin expression in human neurons.

Zachary M Augur, Garrett M Fogo, Mason R Arbery, Andrew M Stern, Courtney R Benoit, Yi-Chen Hsieh, Tracy L Young-Pearse.

  Optineurin (OPTN) is an autophagy adaptor protein involved in selective autophagy, including aggrephagy and mitophagy. Pathogenic mutations in OPTN have also been linked to amyotrophic lateral sclerosis, frontotemporal dementia, and glaucoma, supporting its role in the etiology of neurodegenerative diseases. Despite its established biological roles, knowledge about its potential contribution to Alzheimer's disease (AD) pathology and neuronal functioning is lacking. AD is characterized by the accumulation of extracellular amyloid-β plaques and intracellular phosphorylated tau (pTau) tangles, with dysfunction in the autophagy-lysosomal pathway exacerbating tau pathology and impairing proteostasis. To investigate the role of OPTN in neuronal proteostasis and AD, we utilized induced pluripotent stem cell-derived neuron (iN) and astrocyte (iA) models. Analyses revealed a significant negative correlation between OPTN and specific pTau epitopes in neurons, as well as a decrease in OPTN protein abundance in brain tissues of individuals with AD. Given these findings, we generated OPTN knockout (KO), heterozygous, and wildtype iNs and iAs using CRISPR/Cas9 editing of iPSCs in two genetic backgrounds. Loss of OPTN in iNs increased specific pTau proteoforms without substantially affecting autophagy processes or mitochondrial respiration. Despite no clear effect on mitochondrial function, several mitochondrial proteins, including OXCT1, were enriched in an unbiased analysis of the OPTN interactome in iNs, as well as proteins involved in intracellular trafficking. Proteomic analyses further identified intracellular clusterin, an AD risk gene, as significantly upregulated in OPTN KO iNs, suggesting OPTN may influence its intracellular processing. Our model system demonstrates modest roles for OPTN in certain neuronal biological processes and potential implications for AD pathogenesis. These findings also suggest that OPTN may exhibit functional redundancy with other autophagy adaptor proteins in human neurons, leading to relatively mild phenotypic changes with complete loss of OPTN.

Keywords:  Alzheimer’s disease; Autophagy; Clusterin; Optineurin; Tau

DOI:  https://doi.org/10.1186/s40478-025-02103-y
Neural Regen Res. 2025 Sep 03.

TDP-43-immunity-microbiota axis in amyotrophic lateral sclerosis: A potential pathogenic mechanism.

Yasmine Abbassi, Dorian Fink, Francesco Cei, Elena Niccolai, Amedeo Amedei.

   ABSTRACT: Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration. Despite extensive research, effective treatments remain elusive, underscoring the need to explore the molecular mechanisms driving disease progression. The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity, encompassing both genetic and sporadic forms, diverse phenotypic presentations, and highly variable progression rates. A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43, which contributes to cellular toxicity, neuroinflammation, and neuronal dysfunction. This review explores the complex interplay between TAR DNA-binding protein 43 pathology, immunity dysregulation, and the gut-brain axis, with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis. Neuroinflammation, mediated by both innate and adaptive immunity, plays a central role in disease pathogenesis, with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity. Additionally, disruptions in gut microbiota composition and intestinal barrier integrity, frequently observed in amyotrophic lateral sclerosis patients, suggest a potential role for the gut-brain axis in modulating neurodegenerative processes. By integrating evidence from emerging studies, our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease. Understanding these interactions could pave the way for novel therapeutic strategies, including microbiome-targeted interventions such as probiotics, dietary modifications, or immune-modulating therapies. Finally, unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation, slowing amyotrophic lateral sclerosis progression, and improving patient outcomes and life quality.

Keywords:  TAR DNA-binding protein 43; amyotrophic lateral sclerosis; immunity; microbiome; neuroinflammation; short-chain fatty acids

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00440
FEBS Lett. 2025 Sep 01.

C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules.

Saygın Bilican, Yara Nabawi, William Hongyu Zhang, Dunja Petrovic, Markus Wehrmann, Sara Muñoz-García, Seda Koyuncu, David Vilchez.

  Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by motor neuron degeneration. Hexanucleotide repeat expansions in the C9orf72 gene, the most common genetic cause of ALS (C9-ALS), drive toxicity through different mechanisms. These pathological changes include alterations in stress granules (SGs), ribonucleoprotein complexes formed under stress conditions. Here, we show that G3BP1, a core component of SGs, exhibits enhanced interaction with the nucleoporin Nup107 in motor neurons derived from patient iPSCs carrying C9orf72 mutations. Moreover, Nup107 colocalizes with SGs and aggregates in C9-ALS motor neurons. Notably, knockdown of npp-5, the Caenorhabditis elegans ortholog of Nup107, alleviates ALS-associated phenotypes in worm models, including reduced lifespan and impaired motility. Together, our findings provide insights into disease-related changes in C9-ALS pathogenesis.

Keywords:  Amyotrophic lateral sclerosis; C. elegans; Nucleoporins; Proteostasis; Stress granules; iPSC‐disease modeling

DOI:  https://doi.org/10.1002/1873-3468.70156
J Cell Biol. 2025 Oct 06. pii: e202410130. [Epub ahead of print]224(10):

Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.

Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gracie Manigault, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.

Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondrial dynamics as a critical step in neurodevelopment.

DOI: https://doi.org/10.1083/jcb.202410130
FASEB J. 2025 Aug 31. 39(16): e70958

Intracellular and Extracellular Vesicle miRNA Signatures in Human iPSC-Derived Neural Stem Cells and Floor Plate Progenitors.

Lilian Cruz, Frederico Moraes Ferreira, Camila Miranda Lopes-Ramos, Zhiyun Wei, William T Hendriks, H A Jinnah, Helder I Nakaya, D Cristopher Bragg, Anna M Krichevsky, Xandra Owens Breakefield, Marilene Hohmuth Lopes.

  Refined control of intrinsic and extrinsic signals is critical for specific neuronal differentiation. Here, we differentiated human induced pluripotent stem cells (hiPSCs) from three different healthy donors into neural stem cells (NSCs) and floor plate progenitors (FPPs; progenitors of dopaminergic neurons) and further performed intracellular and extracellular vesicles' (EVs) miRNA profiling. While NSC and FPP cells differed significantly in levels of only 8 intracellular miRNAs, their differences were more evident in the EV miRNAs with 27 differentially expressed miRNAs. Target validation of intracellular miRNAs revealed that FPPs expressed more EXOC5 mRNA than NSCs, which is implicated in the function of primary cilia, an essential signaling organelle in FPPs. Moreover, we found a group of 5 miRNAs consistently enriched in EVs from these three cell types. This study presents a foundation for the field of miRNA regulation in neural development and provides new insights for disease modeling and regenerative medicine.

Keywords:  EXOC5; dopaminergic neurons; exosomes; floor plate progenitors; human induced pluripotent stem cells; microRNA; neural differentiation; neuronal development

DOI:  https://doi.org/10.1096/fj.202501157R
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2505320122

De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation.

Gangyu Sun, Xiang Li, Jiaojiao Hu, Tianbin Yang, Cong Liu, Zhizhi Wang, Dan Li, Wenqing Xu.

  Pathological aggregation of transactive response DNA binding protein of 43 kDa (TDP-43), primarily driven by its low-complexity domain, is closely associated with various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the therapeutic potential of preventing TDP-43 aggregation, no effective small molecule or biomacromolecule therapeutics have been successfully developed so far. Here, we introduce a protein design strategy that yields de novo designed proteins capable of stabilizing the key amyloidogenic region of TDP-43 in its native helical conformation with nanomolar binding affinity. The binding mechanism was further characterized by the NMR and mutagenesis study. More importantly, we demonstrated that our designed protein binders efficiently reduced TDP-43 amyloid aggregation both in vitro and in cells. Our work provides a strategy for designing protein stabilizer of the native conformation of pathological proteins for preventing its amyloid aggregation, shedding light on the development of potential therapeutic approaches for ALS, FTLD, and other protein aggregation-associated diseases.

Keywords:  TDP-43; neural degenerative disease; protein design

DOI:  https://doi.org/10.1073/pnas.2505320122
J Neurochem. 2025 Sep;169(9): e70214

Restoration of Lysosomal Hydrolase Activities by LRRK2 Inhibition in GBA1- and LRRK2-Associated Parkinson's Disease Patient-Derived Cells.

T S Usenko, K S Basharova, A I Bezrukova, E V Grigor'eva, S V Pavlova, G V Baydakova, M A Nikolaev, I N Gaponenko, O V Khegay, I V Miliukhina, E Yu Zakharova, S N Pchelina.

  Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), and the LRRK2 gene, encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). The potential use of LRRK2 inhibitors for treating not only LRRK2-associated PD (LRRK2-PD) but also GBA1-associated PD (GBA1-PD) is currently under discussion. In the present study, we aimed to evaluate whether LRRK2 inhibition affects lysosomal hydrolase enzymatic activities, autophagy, and alpha-synuclein levels in various cell types derived from LRRK2-PD and GBA1-PD patients, including macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages), dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSC-derived DA neurons), and SH-SY5Y cells. We first characterized PBMC-derived macrophages from patients with LRRK2-PD. Confocal microscopy revealed reduced colocalization of GCase with the lysosomal marker LAMP2, indicating impaired lysosomal translocation of the enzyme. In parallel, we observed decreased activity of galactosylceramidase (GALC), increased levels of lysosphingolipids (HexSph, LysoGb3, LysoSM) as measured by LC-MS/MS, and decreased pro-form of cathepsin D, as assessed by Western blot analysis, compared to controls. However, no significant differences in GCase activity and protein levels were observed in PBMC-derived macrophages of LRRK2-PD patients and controls. In subsequent experiments, we found that LRRK2 inhibition not only increased GCase activity in both PBMC-derived macrophages and iPSC-derived DA neurons but also augmented the activity of other lysosomal enzymes, including acid sphingomyelinase (ASMase), alpha-galactosidase (GLA), and GALC. Notably, this enhancement was more pronounced in iPSC-derived DA neurons compared to PBMC-derived macrophages. Similar increases in lysosomal hydrolase activities (GCase, ASMase, GALC, and GLA) were also observed in the SH-SY5Y neuroblastoma cell line after LRRK2 inhibition. Interestingly, LRRK2 inhibition was more effective in GBA1-PD than in LRRK2-PD. We demonstrated that LRRK2 inhibition enhances both the protein levels of GCase and its translocation to lysosomes. This study provides the first evidence that inhibition of LRRK2 activity may increase GCase level and its translocation to lysosomes, thereby ameliorating lysosomal function. Moreover, LRRK2 inhibition also enhances the activity of other lysosomal hydrolases. Our findings expand the understanding of the molecular mechanism of LRRK2 inhibitors, offering valuable insights for further development of PD treatments.

Keywords:  MLi‐2; Parkinson disease; alpha‐synuclein; glucocerebrosidase; leucine‐rich repeat kinase 2; lysosomal hydrolases

DOI:  https://doi.org/10.1111/jnc.70214
CNS Drugs. 2025 Sep 02.

Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.

Savannah E Quigley, Kellen H Quigg, Stephen A Goutman.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.

DOI: https://doi.org/10.1007/s40263-025-01217-0
Neurochem Res. 2025 Sep 04. 50(5): 284

Wnt7b Promotes Axon Differentiation and Extension by Regulating JNK-Mediated Cytoskeletal Dynamics.

Lorena P Neila, Sebastian Luna, Rodrigo Vena, Silvana B Rosso.

  Neuronal polarization and axon growth are critical processes underlying neuronal differentiation and maturation. Wnt proteins have been implicated as key regulators of neuronal development; however, the cellular mechanisms through which they influence axon growth remain poorly understood. In this study, we investigated the role of Wnt7b in axon differentiation and elongation in hippocampal neurons, and aimed to characterize the underlying molecular mechanisms involved. Our results show that Wnt7b accelerates neuronal polarization and promotes axon elongation. In the presence of Wnt7b, most undifferentiated neurons polarized and subsequently developed longer axons compared to controls. Further analysis revealed that this effect is mediated by the JNK signaling pathway, as both pharmacological inhibition and expression of a dominant-negative JNK construct blocked Wnt7b-induced axonal elongation. Additionally, Wnt7b triggered local activation of JNK in growing axons and induced cytoskeletal rearrangements. Specially, Wnt stimulation promoted microtubule stabilization along newly formed axons and enhanced the protrusion of dynamic microtubules into the growth cones, a process that may facilitate axon extension. Together, these findings identify Wnt7b as a crucial modulator of axon differentiation and elongation, acting through activation of the JNK pathway.

Keywords:  Axon; Growth cone; JNK; Microtubule stability; Neuronal polarity; Wnt proteins

DOI:  https://doi.org/10.1007/s11064-025-04540-6
Am J Hum Genet. 2025 Aug 26. pii: S0002-9297(25)00310-6. [Epub ahead of print]

Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models.

Yu-Ju Lee, Ya-Ting Chang, Yoobin Cho, Max Kowalczyk, Adrian Dragoiescu, Alain Pacis, Senthilkumar Kailasam, François Lefebvre, Qihuang Zhang, Xiaojing Gao, Wei-Hsiang Huang.

  Smith-Magenis syndrome (SMS) is a genomic disorder caused by the deletion of a chromosomal region at 17p11.2. Individuals with SMS are frequently diagnosed with autism and have profound cortical deficits, including reduced cortex volume, mild ventriculomegaly, and epilepsy. Here, we developed human induced pluripotent stem cell (hiPSC)-derived neuronal models to understand how del(17)p11.2 affects cortical development. Hi-C experiments identified local fusion and global reorganization of topological domains, as well as genome-wide miswiring of chromatin three-dimensional (3D) interactions in SMS hiPSCs and 3D cortical organoids. Single-nucleus RNA sequencing of SMS cortical organoids identified neuropsychiatric disease-enriched transcriptional signatures and dysregulation of genes involved in catabolic and biosynthetic pathways, cell-cycle processes, and neuronal signaling. SMS cortical organoids displayed reduced growth, enlarged ventricles, impaired cell-cycle progression, and accelerated neuronal maturation. Through the use of a complementary hiPSC-derived 2D cortical neuronal model, we report that SMS cortical neurons exhibited accelerated dendritic growth, followed by neuronal hyperexcitability associated with reduced potassium conductance. Our study demonstrates that del(17)p11.2 disrupts multiple steps of human cortical development, from chromatin wiring, transcriptional regulation, cell-cycle progression, and morphological maturation to neurophysiological properties, and hiPSC-derived models recapitulate key neuroanatomical and neurophysiological features of SMS.

Keywords:  CNV; Hi-C; RAI1; SMS; Smith-Magenis syndrome; autism; cortical organoids; human stem cells; iPSC; retinoic acid-induced 1

DOI:  https://doi.org/10.1016/j.ajhg.2025.07.020
Am J Pathol. 2025 Aug 26. pii: S0002-9440(25)00300-1. [Epub ahead of print]

The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.

Dariusz Pytel, Jody Fromm Longo.

  Proteinopathies are neurodegenerative disorders that are characterized by accumulation of misfolded toxic protein aggregates that lead to synaptic and neuronal dysfunction. Though genetically, clinically and pathologically distinct, a common feature of these diseases is disruption of protein homeostasis (proteostasis), which causes accumulation of misfolded proteins. The machinery mediating proteostasis exquisitely balances and interlaces protein synthesis, protein folding and trafficking, and protein degradation processes within the proteostasis network to maintain homeostasis. The proteostasis network governs a functional and dynamic proteome by modulating the timing, location, and stoichiometry of protein expression, surveillance and maintenance of protein folding and removal of misfolded or excess proteins. Although a functional proteome is essential for the health of all cell types, this is especially true for neurons which are prone to enhanced cellular stress. Aging is the most important risk factor for proteostasis decline and the development of proteinopathies. However, germline and somatic mutations can also functionally impair components of the proteostasis network. Post-mitotic cells, particularly neurons, are rendered further susceptible to proteostasis dysfunction due to their extended lifespan. This review discusses the interconnections between the functional components mediating proteostasis in neuronal cells and how aberrations in proteostasis contribute to neuronal dysfunction and disease.

Keywords:  Alzheimer’s Disease; Amyotrophic Lateral Sclerosis; ER stress; ERAD; Frontotemporal Dementia; Huntington’s Disease; Parkinson’s Disease; UPR; aggregates; autophagy; protein homeostasis; proteinopathies

DOI:  https://doi.org/10.1016/j.ajpath.2025.07.011
Protein J. 2025 Aug 30.

Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease.

Apoorva Pai Kalasa Anil Kumar, Suhail Subair, Prathik Basthikoppa Shivamurthy, Samseera Ummar, Athira C Rajeev, Rajesh Raju.

  Ataxin-2 (ATXN2), a key RNA-binding protein, regulates RNA metabolism, stress granule formation, and neuronal homeostasis, with dysregulated phosphorylation contributing to Spinocerebellar Ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and cancer. This review integrates structural biology, phosphoproteomics, and interactome analyses to map six critical phosphosites (S772, T741, S624, S684, S784, S889) within ATXN2's intrinsically disordered regions. Modulated by kinases GSK3β and CDK13 and phosphatases like INPP5F, these sites orchestrate interactions with RNA-binding partners (e.g., ATXN2L, FXR2, STAU2) and co-regulated proteins (e.g., TP53BP1, NUP153), driving pathogenesis through disrupted autophagy, nucleocytoplasmic transport, and stress granule dynamics. We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.

Keywords:  Amyotrophic lateral sclerosis; Ataxin-2; Phosphoproteomics; Spinocerebellar Ataxia type 2

DOI:  https://doi.org/10.1007/s10930-025-10287-4
Neurogenetics. 2025 Sep 06. 26(1): 66

Huntington's chorea: emerging fields in therapeutics (Review).

Aisha Tahir, Sania Jamal, Usman Ali Shams, Saqib Mehmood.

  Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric disturbances. It is caused by CAG repeat expansions in the HTT gene, resulting in the formation of mutant huntingtin protein that aggregates and disrupts neuronal function. This review outlines the pathogenesis of HD, including genetic, molecular, and environmental factors. Additionally, current management approaches and emerging therapeutic strategies-such as RNA interference, antisense oligonucleotides (ASOs), peptide inhibitors, and CRISPR/Cas9 gene editing-are discussed. Advancements in these novel therapies highlight a shift towards disease-modifying interventions. However, continued clinical and translational research is essential to develop a definitive cure.

Keywords:  ASO; CAG repeat; CRISPR; Gene therapy; HTT gene; Huntington’s disease; RNAi

DOI:  https://doi.org/10.1007/s10048-025-00848-1
FEBS J. 2025 Sep 02.

TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.

Ghulam Jeelani Pir, Joerg Buddenkotte, Majid Ali Alam, Ahmed Own, Randall J Eck, Brian C Kraemer, Eckhard Mandelkow, Martin Steinhoff.

  TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.

Keywords:  Alzheimer's disease (AD); C. elegans; GABA; G‐protein coupled receptors; Huntington's disease; Parkinson's disease (PD); TDP‐43/TDP‐1; acetylcholine; amyotrophic lateral sclerosis (ALS); extracellular vesicles (EV); frontotemporal dementia (FTD); ion channels; limbic‐predominant age‐related TDP‐43 encephalopathy (LATE); proteinopathies; tau

DOI:  https://doi.org/10.1111/febs.70239
Cell Mol Life Sci. 2025 Aug 29. 82(1): 325

Loss of synaptic Munc13-1 underlies neurotransmission abnormalities in spinal muscular atrophy.

Mehri Moradi, Chunchu Deng, Michael Sendtner.

  Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease characterized by degeneration of spinal motoneurons, leading to muscle atrophy and synaptic loss. SMN functions in mRNA splicing, transport, and local translation are crucial for maintaining synaptic integrity. Within the presynaptic membrane, the active zone orchestrates the docking and priming of synaptic vesicles. The Munc13 family proteins are key active zone components that operate precise neurotransmitter release in conjunction with voltage-gated Ca2+ channels (VGCCs). However, the role of Munc13s in synaptic dysfunction in SMA remains elusive. Our findings reveal that Munc13-1 loss, but not Munc13-2, is closely linked to synaptic aberrations in SMA. Specifically, Munc13-1 mRNA localization in axons is dependent on Smn, and its disruption leads to impaired AZ assembly and VGCC clustering in motoneurons, ultimately reducing neuronal activity. In contrast, Munc13-2 does not appear to be essential for AZ assembly or motoneuron differentiation, as its functions can be compensated by Munc13-1. These findings highlight the pivotal role of Munc13-1 in synapse integrity and point to potential therapeutic targets for mitigating synaptic loss in SMA.

Keywords:  Active zone; Axonal mRNA localization; Munc13-2; Survival of motor neuron; Synapse degeneration

DOI:  https://doi.org/10.1007/s00018-025-05859-7
Autophagy Rep. 2025 ;4(1): 2547975

Sequestering sequestosome 1 via S-acylation in autophagy, Huntington disease, and beyond.

Y Alshehabi, F Abrar, D D O Martin.

  Protein mislocalization and aggregation are hallmark features in neurodegeneration. As proteins mislocalize, proteostasis deficiency and protein aggregation typically follow. Autophagy is a crucial pathway for the removal of protein aggregates to maintain neuronal health, but is impaired in various neurodegenerative diseases, including Huntington disease (HD). We identified S-acylation, a reversible lipid modification of proteins, as an important regulator in protein trafficking and autophagy. SQSTM1 (sequestosome 1/p62) is an essential selective autophagy receptor for the sequestration of ubiquitinated cargoes within autophagosomes and subsequent delivery into lysosomes for degradation. Recently, we reported that S-acylation of SQSTM1 at the di-cysteine motif C289,290 directs SQSTM1 to lysosomes. We further showed that SQSTM1 S-acylation is significantly reduced in brains from both HD patients and mouse HD model, which may result in the cargo sequestration defect within autophagosomes in HD. Treatment with palmostatin B, a deacylation inhibitor, significantly increases SQSTM1 localization to lysosomes. Our work highlights SQSTM1 S-acylation as a novel potential therapeutic strategy in HD. As a crucial autophagy component, our work suggests S-acylation of SQSTM1 may have a broader role in neurodegeneration.

Keywords:  Autophagy; Huntington disease; S-acylation; fasting; huntingtin; localization; mouse model; palmitoylation; palmostatin B; sequestosome 1

DOI:  https://doi.org/10.1080/27694127.2025.2547975
Biochem J. 2025 Sep 04. pii: BCJ20253212. [Epub ahead of print]482(17):

Selectivity profiles and substrate recognition of Rab-phosphorylating kinases.

Deep Chatterjee, Verena Dederer, Landon Vu Nguyen, Marcel Wendel, Kamal R Abdul Azeez, Swetha Mahesula, Florian Stengel, Samara Reck-Peterson, Sebastian Mathea.

  The Rab GTPase switch-2 region is a hotspot for post-translational modifications. Its phosphorylation can determine whether individuals develop Parkinson's disease or not. Other modifications of the same region are catalyzed by enzymes from bacterial pathogens when they infect human cells. Here, we profiled a set of kinases including LRRK1, LRRK2, DYRK1A, MST1 and TBK1 for their capability of phosphorylating Rab GTPases. We identified several novel kinase:Rab pairs, such as LRRK1:Rab43 and TBK1:Rab29. Further, we comprehensively assessed what makes a Rab GTPase a good kinase substrate, considering the Rab nucleotide-binding state and the Rab primary sequence. In a systematic mutational study, Rab variants with modulated phosphorylation properties were established, leading to the identification of a LRRK2 recognition patch in the Rab α3 helix. A Glu to Arg exchange in that patch increased the phosphorylation 18-fold, indicating that Rabs are suboptimal LRRK2 substrates. Given that this effect is also observed in a cellular model, we propose that our variants will be excellent tools for analysing the physiological function of Rab phosphorylation.

Keywords:  GTPases; enzyme activity; enzymology; kinases; leucine-rich repeat kinase; synaptic vesicle

DOI:  https://doi.org/10.1042/BCJ20253212
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251372668

MCS Ultrastructural Analyses Using Electron Microscopy.

Atsuki Nara.

  Membrane contact sites (MCSs) are microdomains that exchange ions and lipids between the membranes of two organelles. They facilitate the exchange of metabolites and act as a site for intracellular communication through material transport. Because of the important physiological significance of MCSs in localizing the exchange of substances and metabolic regulation, they are considered to play an important role in cell biology. Understanding MCS structure is essential for analyzing how substances move to and from each organelle. Several methods have been developed to analyze MCS function, with electron microscopy (EM) being the predominant technique when structural detail is needed. In this review, we summarize the ultrastructure of MCSs and how EM can be used to determine their role in cell biology.

Keywords:  ER; autophagosome; contact; electron microscopy; endosome; membrane contact sites; mitochondria; nucleus; plasma membrane; tether

DOI:  https://doi.org/10.1177/25152564251372668
bioRxiv. 2025 Aug 24. pii: 2025.08.19.670962. [Epub ahead of print]

Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved TBM motif.

Dieter Waschbüsch, Prosenjit Pal, Raja S Nirujogi, Melanie Cavin, Jaijeet Singh, Dario R Alessi, Amir R Khan.

Inherited mutations in VPS35 and the kinase LRRK2 lead to hyperphosphorylation of Rab GTPases and promote the formation of phospho-Rab signalling complexes. A subset of RH2 domain-containing proteins from the RILP-homology family, including RILP, RILPL1, RILPL2, JIP3, and JIP4 are Rab effectors that recognize the LRRK2-phosphorylated switch 2 threonine of phospho-Rab8A and phospho-Rab10. More recently, phospho-Rabs have been found on lysosomal membranes within multi-protein assemblies involving TMEM55B and RILPL1. TMEM55B is a 284-residue lysosomal membrane protein with no homology to known proteins. It comprises a 218-residue cytosolic N-terminal region and two predicted transmembrane α-helices. Residues 80-160, which face the cytosol, mediate binding to a C-terminal motif of RILPL1, formed after RILPL1 associates with phospho-Rab8A. Here, we report the crystal structures of TMEM55B alone and in complex with a C-terminal RILPL1 peptide, encompassing the TMEM55B interaction region, which we define as the TMEM55B Binding Motif (TBM). The cytosolic domain of TMEM55B adopts a rigid architecture of two tandem RING-like domains, each forming a Zn2+-stabilized 40-residue β-sandwich. TBM binding is mediated primarily by backbone hydrogen bonding and anchored by two glutamate residues from RILPL1. These findings support a model in which RILPL1 is recruited to phospho-Rab8A-positive lysosomes prior to TMEM55B engagement. Further co-immunoprecipitation and mutational analyses indicate that TMEM55B forms complexes independently of phospho-Rabs with proteins containing a conserved TBM, like that of RILPL1, including JIP3, JIP4, OCRL, WDR81, and TBC1D9B. Together, these findings uncover previously unrecognized regulatory networks associated with TMEM55B and lysosomal function and suggest that TMEM55B serves as a central hub for adaptor recruitment at the lysosomal membrane.

DOI: https://doi.org/10.1101/2025.08.19.670962
bioRxiv. 2025 Aug 25. pii: 2025.08.21.671404. [Epub ahead of print]

An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.

Olivia Gautier, Jacob A Blum, Thao P Nguyen, Sandy Klemm, Mai Yamakawa, Nasa Sinnott-Armstrong, Yi Zeng, Chung-Ha O Davis, Juliane Bombosch, Lisa Nakayama, Kevin A Guttenplan, Derek Chen, Arwa Kathira, Luke Zhao, Jessica E Rexach, William J Greenleaf, Aaron D Gitler.

To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.

DOI: https://doi.org/10.1101/2025.08.21.671404
HGG Adv. 2025 Aug 27. pii: S2666-2477(25)00101-0. [Epub ahead of print] 100498

Targeted plasma proteomics uncover proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders.

Jarosław Dulski, Arun K Boddapati, Barbara Risi, Pablo Iruzubieta, Antonio Orlacchio, Roberto Fernández-Torrón, Tamara Castillo-Triviño, Adolfo López de Munain, Steve Vucic, Alessandro Padovani, Laura Donker Kaat, Tahsin Stefan Barakat, Leonard Petrucelli, Mercedes Prudencio, John E Landers, Jochen H Weishaupt, Andreas Prokop, Massimiliano Filosto, Zbigniew K Wszolek, Devesh C Pant.

KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10, ALS individuals and compared to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function, and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 individuals. Moreover, these findings can now be taken forward to gain mechanistic understanding of axonopathies linking to N- versus C-terminal KIF5A variants affecting both central and peripheral nervous systems.

DOI: https://doi.org/10.1016/j.xhgg.2025.100498
Sci Adv. 2025 Sep 05. 11(36): eadt4126

Synaptic imbalance and increased inhibition impair motor function in SMA.

Emily V Fletcher, Joshua I Chalif, Travis M Rotterman, John G Pagiazitis, Meaghan Van Alstyne, Nandhini Sivakumar, Danny Florez-Paz, Joseph E Rabinowitz, Livio Pellizzoni, Francisco J Alvarez, George Z Mentis.

Movement is executed through balanced excitation-inhibition in spinal motor circuits. Short-term perturbations in one type of neurotransmission are homeostatically counteracted by the opposing type, but prolonged excitation-inhibition imbalance causes dysfunction at both single neuron and circuit levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used functional, morphological, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable SMA motor circuits fail to respond homeostatically to reduced excitation and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment. Reducing inhibition genetically or pharmacologically improves neuronal function and motor behavior in SMA mice. Thus, the disruption of excitation-inhibition homeostasis is a major maladaptive mechanism that diminishes the capacity of premotor commands to recruit motor neurons and elicit muscle contractions in SMA.

DOI: https://doi.org/10.1126/sciadv.adt4126
J Biol Chem. 2025 Sep 02. pii: S0021-9258(25)02527-X. [Epub ahead of print] 110675

Ubiquitin-specific protease 7 promotes the growth and oncogenic potential of acute myeloid leukemia cells through the deubiquitination and upregulation of LRRK2.

Joon Hyung Park, Kwang Chul Chung.

  Leucine-rich repeat kinase 2 (LRRK2), a large protein with kinase and GTPase activities, regulates various cellular pathways, including autophagy, endocytosis, and mitochondrial dynamics. LRRK2, extensively studied in the context of Parkinson's disease, is functionally impaired in other pathological conditions as well, including inflammatory bowel disease, cancer, and cardiovascular diseases. Despite its critical functions, the mechanisms controlling LRRK2 protein stability are not fully understood. Recent studies suggest that the ubiquitin-proteasome system (UPS) plays a key role in regulating LRRK2 stability. However, the relationship between deubiquitinating enzymes (DUBs) and LRRK2 has not been fully understood. In this study, we identified ubiquitin-specific protease 7 (USP7) as the novel DUB that positively regulates LRRK2 by preventing its degradation through UPS. We demonstrated that USP7 directly binds to LRRK2 and promotes its accumulation by deubiquitinating K48-linked polyubiquitin chains. Notably, among various types of cancer, the highest and most significant expression of these two genes was observed in acute myeloid leukemia (AML). We also found that inhibition or knockdown of USP7 suppressed AML cell growth via down-regulation of LRRK2, and this effect was partially reversed by LRRK2 overexpression. Furthermore, LRRK2 overexpression significantly increased both the colony formation and cell invasion rates in AML cells, compared to the down-regulation of USP7. Taken together, our findings identify USP7 as a novel deubiquitinating enzyme of LRRK2 that positively regulates its stability and plays an oncogenic role in AML, with implications for AML cancer progression and potential therapeutic targets.

Keywords:  AML; Cancer; Deubiquitinating enzyme; LRRK2; USP7; Ubiquitination

DOI:  https://doi.org/10.1016/j.jbc.2025.110675
J Cell Biol. 2025 Sep 03. pii: e202504027. [Epub ahead of print]224(11):

Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics.

Anbang Dai, Peng Xu, Chase Amos, Kenshiro Fujise, Yumei Wu, Han Yang, Julia N Eisen, Andrés Guillén-Samander, Pietro De Camilli.

BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the ER with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. Our findings suggest that mediating bulk lipid transport between the ER and the PM is a key function of this protein, as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM and that it also tethers the ER to macropinosomes in the process of fusing with the PM. We further identify interactions underlying binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A/FAM102B, and N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the PM, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics.

DOI: https://doi.org/10.1083/jcb.202504027
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)00996-9. [Epub ahead of print]44(9): 116225

Mask protein keeps NF-κB precursor inactive by inducing a closed conformation and isolating it in biomolecular condensates.

Kewei Zheng, Xiawei Huang, Xiaojiang Yang, Jiahui Wang, Minhuang Hu, Chengfang Wu, Bo Liu.

  Nuclear factor κB (NF-κB) family transcription factors are critical for innate immune responses across a variety of organisms and are frequently dysregulated in diseases. Understanding their homeostatic regulation is essential for developing therapeutic strategies. Relish, a Drosophila homolog of mammalian NF-κB precursors, provides a valuable model for studying these processes. Although the activation of Relish upon stimulus is well-understood, the mechanisms maintaining its inactivity in the resting state remain unclear. Here, we identify the ankyrin repeat protein multiple ankyrin repeats single KH domain (Mask) as an inhibitor of Relish. Mask binds directly to Relish, facilitating it in a closed conformation, and forms biomolecular condensates that spatially segregate Relish from death-related ced-3/Nedd2-like protein (DREDD), a caspase necessary for Relish activation. Upon immune stimulation, Mask dissociates from Relish and is cleaved by DREDD, thus relieving the inhibition. Notably, Mask's regulatory role is partially conserved in mammals. Our findings provide important insights into NF-κB regulation and highlight the significance of biomolecular condensates in immune control.

Keywords:  CP: Immunology; CP: Molecular biology; DREDD; Drosophila; IMD pathway; NF-κB; biomolecular condensate; innate immunity; liquid-liquid phase separation; mask; p100/p105; relish

DOI:  https://doi.org/10.1016/j.celrep.2025.116225
Front Immunol. 2025 ;16 1659947

The dual nature of neuroinflammation in networked brain.

Ludmila Müller, Svetlana Di Benedetto, Viktor Müller.

  Neuroinflammation is a dynamic, context-sensitive process that plays essential roles in brain development, maintenance, and response to injury. It reflects a finely balanced neuroimmune state-facilitating repair and adaptation under homeostatic conditions, while also contributing to dysfunction when dysregulated or chronically activated. In this mini-review, we examine the cellular and molecular mechanisms underlying neuroinflammatory responses, focusing on the roles of microglia and astrocytes, their bidirectional communication with neurons, and their interaction with peripheral immune signals. We describe how various stimuli-including aging, protein aggregates, and cellular stress-modulate glial function and shift immune activity toward protective or deleterious outcomes. Special attention is given to endogenous regulatory pathways, including cytokine signaling, receptor-mediated crosstalk, and immunometabolic cues that determine the resolution or persistence of inflammation. We further discuss shared and disease-specific features of neuroinflammation across neurological disorders, offering a systems-level perspective on how immune activity contributes to neural resilience or degeneration. This integrated view aims to inform future studies on neuroimmune dynamics in health and disease.

Keywords:  CNS; astrocytes; brain; microglia; neuroimmune interactions; neuroinflammation; neurological disorders; neurons

DOI:  https://doi.org/10.3389/fimmu.2025.1659947
Adv Exp Med Biol. 2025 ;1478 51-60

Mitochondrial Quality Control.

Yuntian Guan, Zhen Yan.

  Mitochondria, the power plants of cells, are essential for various cellular functions. In skeletal muscle, mitochondria form a network, called mitochondrial reticulum, which fuels muscle contractile and metabolic functions. The high degree of structure-to-function specialization of mitochondria in skeletal muscle implies that it is closely gauged and regulated to maintain energy production capacity to match the functional demands. The processes that regulate the overall structure and function of mitochondrial reticulum are collectively referred to as mitochondrial quality control. Mitochondrial quality control consists of mitochondrial biogenesis, dynamics (i.e., fission and fusion), and selective degradation via proteolysis and mitophagy. In this chapter, we will discuss different aspects of contemporary understanding of mitochondrial quality control, their respective mechanisms, and their adaptability to exercise training.

Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial reticulum; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1007/978-3-031-88361-3_3
J Adv Res. 2025 Sep 04. pii: S2090-1232(25)00676-9. [Epub ahead of print]

Role of Netrin-1 dysregulation in early neuronal pathology of α-synuclein models of Parkinson's disease.

Wenjing Han, Tiantian Wang, Ningping Tan, Haixin Liu, Peicheng He, Ye Hua, Yi Fan.

   INTRODUCTION: Parkinson's disease (PD) is characterized by early synaptic and axonal dysfunction, driven by α-synuclein (α-Syn, encoded by the SNCA gene) aggregation. The axon guidance molecules play critical roles in neuronal integrity, yet their dysregulation in PD remains underexplored.
OBJECTIVES: This study aimed to demonstrate how α-Syn preformed fibrils (PFFs) alter the expression of axon guidance molecules, contributing to early synucleinopathy, and to evaluate the therapeutic potential of netrin-1 (NTN1).
METHODS: Transgenic hSNCANestin mice and PFF-injected models were used. Behavioral assessments, Western blot analyses, and immunofluorescence quantified the expression of axon guidance molecules and neuronal morphology at multiple time points.
RESULTS: In hSNCANestin mice, NTN1 mRNA and protein levels decreased significantly at 8 months, while deleted in colorectal cancer (DCC) increased, correlating with reduced dendritic length, spine density, and synaptic proteins. PFF-injected mice showed similar NTN1 reduction and DCC elevation at 6 months, alongside motor deficits and tyrosine hydroxylase-positive (TH+) neuron loss. Exogenous NTN1 application reversed morphological deficits in SH-SY5Y cells and primary neurons exposed to α-Syn PFFs, highlighting its protective role.
CONCLUSION: α-Syn-induced NTN1 reduction exacerbates early PD pathology by impairing axonal and synaptic integrity, while NTN1 restoration mitigates these effects, suggesting therapeutic potential. These findings emphasize axon guidance pathways as key contributors to PD pathogenesis and targets for disease-modifying strategies.

Keywords:  Deleted in colorectal cancer; Netrin-1; Neurodegeneration; Parkinson’s disease; Synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1016/j.jare.2025.08.061