bims-axbals 2024-01-07 papers

bims-axbals

Biomed News

on Axonal Biology and ALS

Issue of 2024‒01‒07
twenty-six papers selected by
TJ Krzystek, ALS Therapy Development Institute

Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.
Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.
Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.
Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.
Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.
A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks.
Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.
4R MAPT/tau drives endolysosomal and autophagy dysfunction in frontotemporal dementia.
Phosphomimetic substitutions in TDP-43's transiently α-helical region suppress phase separation.
A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior.
NOCICEPTRA2.0 - A comprehensive ncRNA atlas of human native and iPSC-derived sensory neurons.
Humanized brain organoids-on-chip integrated with sensors for screening neuronal activity and neurotoxicity.
Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival.
Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples.
Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition.
G3BP1 Interact with JAK2 mRNA to Promote the Malignant Progression of Nasopharyngeal Carcinoma via Activating JAK2/STAT3 Signaling Pathway.
Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera.
Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.
Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.
3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
Phospholipids and Cholesterol Determine Molecular Mechanisms of Cytotoxicity of α-Synuclein Oligomers and Fibrils.
The biology of mitochondrial carrier homolog 2.
Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis.
Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.
Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases.
VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.

Cell Death Dis. 2024 Jan 04. 15(1): 4

Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.

Meng-Lu Liu, Shuaipeng Ma, Wenjiao Tai, Xiaoling Zhong, Haoqi Ni, Yuhua Zou, Jingcheng Wang, Chun-Li Zhang.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

DOI: https://doi.org/10.1038/s41419-023-06395-7
Front Neurosci. 2023 ;17 1319706

Fundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis.

Shumin Zhao, Ranran Chen, Ying Gao, Yanchao Lu, Xue Bai, Jingjing Zhang.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons (MNs) in the brain and spinal cord. It is caused by multiple factors, including mutations in any one of several specific genes. Optineurin (OPTN) mutation is an essential cause of some familial and sporadic ALS. Besides, as a multifunctional protein, OPTN is highly expressed and conserved in the central nervous system. OPTN exerts its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more core proteins related to autophagy and inflammation, etc. OPTN mutation mainly results in its function deficiency, which alters these interactions, leading to functional impairment in many processes. Meanwhile, OPTN immunopositive inclusions are also confirmed in the cases of ALS due to C9ORF72, FUS, TARDBP, and SOD1 mutations. Therefore, OPTN gene may play fundamental roles in the molecular pathology of ALS in addition to OPTN mutation. In this review, we summarize the recent advances in the ALS pathology of OPTN defect, such as mitophagy disorder, neuroinflammation, neuronal axonal degeneration, vesicular transport dysfunction, etc., which will provide a reference for research on the pathogenesis and treatment of ALS.

Keywords:  amyotrophic lateral sclerosis; mitophagy; neuroinflammation; optineurin; protein aggregation

DOI:  https://doi.org/10.3389/fnins.2023.1319706
Acta Neuropathol. 2024 Jan 03. 147(1): 6

Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.

Yingli Zhu, Thibaut Burg, Katrien Neyrinck, Tim Vervliet, Fatemeharefeh Nami, Ellen Vervoort, Karan Ahuja, Maria Livia Sassano, Yoke Chin Chai, Arun Kumar Tharkeshwar, Jonathan De Smedt, Haibo Hu, Geert Bultynck, Patrizia Agostinis, Johannes V Swinnen, Ludo Van Den Bosch, Rodrigo Furtado Madeiro da Costa, Catherine Verfaillie.

  Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late-onset ALS. Although ALS results from MN death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a R521H or a P525L mutation in FUS and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette. Mutant and control iPSCs differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Lipidomic studies demonstrated defects in myelin-related lipids, with a reduction of glycerophospholipids in mutant OPCs. Interestingly, FUSR521H OPCs displayed a decrease in the phosphatidylcholine/phosphatidylethanolamine ratio, known to be associated with maintaining membrane integrity. A proximity ligation assay further indicated that mitochondria-associated endoplasmic reticulum membranes (MAM) were diminished in both mutant FUS OPCs. Moreover, both mutant FUS OPCs displayed increased susceptibility to ER stress when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate a pathological role of mutant FUS in OPCs, causing defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and with suppressed physiological Ca2+ signaling. As such, further exploration of the role of oligodendrocyte dysfunction in the demise of MNs is crucial and will provide new insights into the complex cellular mechanisms underlying ALS.

Keywords:  Amyotrophic lateral sclerosis; ER stress; FUS; Lipid defects; MAM disruption; Mitochondrial dysfunction

DOI:  https://doi.org/10.1007/s00401-023-02666-x
bioRxiv. 2023 Dec 13. pii: 2023.12.12.571299. [Epub ahead of print]

Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.

Jeffrey D Rothstein, Caroline Warlick, Alyssa N Coyne.

The nuclear depletion and cytoplasmic aggregation of the RNA binding protein TDP-43 is widely considered a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and related neurodegenerative diseases. Recent studies have artificially reduced TDP-43 in wildtype human neurons to replicate loss of function associated events. Although this prior work has defined a number of gene expression and mRNA splicing changes that occur in a TDP-43 dependent manner, it is unclear how these alterations relate to authentic ALS where TDP-43 is not depleted from the cell but miscompartmentalized to variable extents. Here, in this population study, we generate ∼30,000 qRT-PCR data points spanning 20 genes in induced pluripotent stem cell (iPSC) derived neurons (iPSNs) from >150 control, C9orf72 ALS/FTD, and sALS patients to examine molecular signatures of TDP-43 dysfunction. This data set defines a time dependent and variable profile of individual molecular hallmarks of TDP-43 loss of function within and amongst individual patient lines. Importantly, nearly identical changes are observed in postmortem CNS tissues obtained from a subset of patients whose iPSNs were examined. Notably, these studies provide evidence that induction of nuclear pore complex (NPC) injury via reduction of the transmembrane Nup POM121 in wildtype iPSNs is sufficient to phenocopy disease associated signatured of TDP-43 loss of function thereby directly linking NPC integrity to TDP-43 loss of function. Therapeutically, we demonstrate that the expression of all mRNA species associated with TDP-43 loss of function can be restored in sALS iPSNs via two independent methods to repair NPC injury. Collectively, this data 1) represents a substantial resource for the community to examine TDP-43 loss of function events in authentic sALS patient iPSNs, 2) demonstrates that patient derived iPSNs can accurately reflect actual TDP-43 associated alterations in patient brain, and 3) that targeting NPC injury events can be preclinically and reliably accomplished in an iPSN based platform of a sporadic disease.

DOI: https://doi.org/10.1101/2023.12.12.571299
Acta Neuropathol. 2024 Jan 04. 147(1): 9

Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.

Ana Rita Agra Almeida Quadros, Zhaozhi Li, Xue Wang, I Sandra Ndayambaje, Sandeep Aryal, Nandini Ramesh, Matthew Nolan, Rojashree Jayakumar, Yi Han, Hannah Stillman, Corey Aguilar, Hayden J Wheeler, Theresa Connors, Jone Lopez-Erauskin, Michael W Baughn, Ze'ev Melamed, Melinda S Beccari, Laura Olmedo Martínez, Michael Canori, Chao-Zong Lee, Laura Moran, Isabelle Draper, Alan S Kopin, Derek H Oakley, Dennis W Dickson, Don W Cleveland, Bradley T Hyman, Sudeshna Das, Nilüfer Ertekin-Taner, Clotilde Lagier-Tourenne.

  Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.

Keywords:  Alzheimer’s disease; Cryptic exons; SCG-10; Stathmin-2; TARDBP; TDP-43; UNC13A

DOI:  https://doi.org/10.1007/s00401-023-02655-0
Genes Dev. 2024 Jan 05.

A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks.

Yeon J Lee, Donald C Rio.

  Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity domain (LCD) of hnRNPA1 can cause splicing changes of thousands of transcripts that collectively are linked to the DNA damage response, cilium organization, and translation. We show that the hnRNPA1 D262V mutant protein binds to new binding sites on differentially spliced transcripts from genes that are linked to ALS. We demonstrate that this ALS-linked hnRNPA1 mutation alters normal RNA-dependent protein-protein interactions. Furthermore, cells expressing this hnRNPA1 mutant exhibit a cell aggregation phenotype, markedly reduced growth rates, changes in stress granule kinetics, and aberrant growth of neuronal processes. This study provides insight into how a single amino acid mutation in a splicing factor can alter RNA splicing networks of genes linked to ALS.

Keywords:  ALS; TMT-MS; amyotrophic lateral sclerosis; hnRNPA1; hnRNPA1 D262V mutant; irCLIP; pre-mRNA splicing

DOI:  https://doi.org/10.1101/gad.351104.123
J Pathol. 2024 Jan 05.

Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.

Ross Ferguson, Michael A van Es, Leonard H van den Berg, Vasanta Subramanian.

  Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  Angiogenin; cortical organoids; induced pluripotent stem cells; neural stem cells; protein synthesis

DOI:  https://doi.org/10.1002/path.6244
Autophagy. 2024 Jan 04.

4R MAPT/tau drives endolysosomal and autophagy dysfunction in frontotemporal dementia.

Christy Hung, Rickie Patani.

  Dysfunction of the neuronal endolysosome and macroautophagy/autophagy pathway is emerging as an important pathogenic mechanism in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The VCP (valosin-containing protein) gene is of significant relevance, directly implicated in both FTD and ALS. In our recent study, we used patient-derived stem cells to study the effects of VCP mutations on the endolysosome and autophagy system in human cortical excitatory neurons. We found that VCP mutations cause an abnormal accumulation of enlarged endosomes and lysosomes, accompanied by reduced autophagy flux. VCP mutations also lead to the spatial dissociation of intra-nuclear RNA-binding proteins, FUS and SFPQ, which correlates with alternative splicing of the MAPT pre-mRNA and increased MAPT/tau phosphorylation. Importantly, we found that an increase in the 4 R-MAPT/tau isoform is sufficient to drive toxic changes in healthy human cortical excitatory neurons, including MAPT/tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress, and apoptosis. Together, our data suggest that endolysosomal and autophagy dysfunction could represent a convergent pathogenic "design principle" shared by both FTD and ALS.

Keywords:  Autophagy; endosomes; lysosome; tau; tauopathy

DOI:  https://doi.org/10.1080/15548627.2023.2300917
Biophys J. 2024 Jan 04. pii: S0006-3495(24)00001-8. [Epub ahead of print]

Phosphomimetic substitutions in TDP-43's transiently α-helical region suppress phase separation.

Raza Haider, Srinivasa Penumutchu, Solomiia Boyko, Witold K Surewicz.

  Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) is present within the aggregates of several age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and Alzheimer's disease, to the point that the presence of phosphorylated TDP-43 is considered a hallmark of some of these diseases. The majority of known TDP-43 phosphorylation sites detected in ALS/FTLD patients is located in the low complexity domain (LCD), the same domain that has been shown to be critical for TDP-43 liquid-liquid phase separation (LLPS). However, the effect of these LCD phosphorylation sites on TDP-43 LLPS has been largely unexplored, and any work that has been done has largely focused on sites near the C-terminal end of the LCD. Here, we used a phosphomimetic approach to explore the impact of phosphorylation at residues S332 and S333, sites located within the transiently α-helical region of TDP-43 that have been observed to be phosphorylated in disease, on protein LLPS. Our turbidimetry and fluorescence microscopy data demonstrate that these phosphomimetic substitutions greatly suppress LLPS, and solution NMR data strongly suggest that this effect is at least in part due to the loss of α-helical propensity of the phosphomimetic protein variant. We also show that the S332D and S333D substitutions slow TDP-43 LCD droplet aging and fibrillation of the protein. Overall, these findings provide a biophysical basis for understanding the effect of phosphorylation within the transiently α-helical region of TDP-43 LCD on protein LLPS and fibrillation, suggesting that phosphorylation at residues 332 and 333 is not necessarily directly related to the pathogenic process.

Keywords:  TAR DNA-binding protein of 43 kDa (TDP-43); amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); intrinsically-disordered protein; liquid-liquid phase separation; neurodegenerative diseases; protein aggregation; protein phosphorylation

DOI:  https://doi.org/10.1016/j.bpj.2024.01.001
Protein Sci. 2023 Dec 31. e4891

A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior.

Priyesh Mohanty, Azamat Rizuan, Young C Kim, Nicolas L Fawzi, Jeetain Mittal.

  TAR DNA-binding protein 43 (TDP-43) is a multidomain protein involved in the regulation of RNA processing, and its aggregates have been observed in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Numerous studies indicate TDP-43 can undergo liquid-liquid phase separation (LLPS) in vitro and is a component of biological condensates. Homo-oligomerization via the folded N-terminal domain (aa:1-77) and the conserved helical region (aa:319-341) of the disordered, C-terminal domain is found to be an important driver of TDP-43 phase separation. However, a comprehensive molecular view of TDP-43 phase separation, particularly regarding the nature of heterodomain interactions, is lacking due to the challenges associated with its stability and purification. Here, we utilize all-atom and coarse-grained (CG) molecular dynamics (MD) simulations to uncover the network of interdomain interactions implicated in TDP-43 phase separation. All-atom simulations uncovered the presence of transient, interdomain interactions involving flexible linkers, RNA-recognition motif (RRM) domains and a charged segment of disordered C-terminal domain (CTD). CG simulations indicate these inter-domain interactions which affect the conformational landscape of TDP-43 in the dilute phase are also prevalent in the condensed phase. Finally, sequence and surface charge distribution analysis coupled with all-atom simulations (at high salt) confirmed that the transient interdomain contacts are predominantly electrostatic in nature. Overall, our findings from multiscale simulations lead to a greater appreciation of the complex interaction network underlying the structural landscape and phase separation of TDP-43. This article is protected by copyright. All rights reserved.

Keywords:  TAR DNA-binding protein 43 (TDP-43); amyotrophic lateral sclerosis (ALS); biomolecular condensates; frontotemporal dementia (FTD); molecular dynamics (MD) simulations; phase separation; phase-coexistence simulations

DOI:  https://doi.org/10.1002/pro.4891
iScience. 2023 Dec 15. 26(12): 108525

NOCICEPTRA2.0 - A comprehensive ncRNA atlas of human native and iPSC-derived sensory neurons.

Maximilian Zeidler, Diana Tavares-Ferreira, Jackson Brougher, Theodore J Price, Michaela Kress.

  Non-coding RNAs (ncRNAs) are pivotal in gene regulation during development and disease. MicroRNAs have been extensively studied in neurogenesis. However, limited knowledge exists about the developmental signatures of other ncRNA species in sensory neuron differentiation, and human dorsal root ganglia (DRG) ncRNA expression remains undocumented. To address this gap, we generated a comprehensive atlas of small ncRNA species during iPSC-derived sensory neuron differentiation. Utilizing iPSC-derived sensory neurons and human DRG RNA sequencing, we unveiled signatures describing developmental processes. Our analysis identified ncRNAs associated with various sensory neuron stages. Striking similarities in ncRNA expression signatures between human DRG and iPSC-derived neurons support the latter as a model to bridge the translational gap between preclinical findings and human disorders. In summary, our research sheds light on the role of ncRNA species in human nociceptors, and NOCICEPTRA2.0 offers a comprehensive ncRNA database for sensory neurons that researchers can use to explore ncRNA regulators in nociceptors thoroughly.

Keywords:  Bioinformatics; Biological database; Biological sciences; Cellular neuroscience; Health sciences; Medicine; Natural sciences; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2023.108525
Mikrochim Acta. 2024 Jan 03. 191(1): 71

Humanized brain organoids-on-chip integrated with sensors for screening neuronal activity and neurotoxicity.

Pelin Saglam-Metiner, Ender Yildirim, Can Dincer, Onur Basak, Ozlem Yesil-Celiktas.

  The complex structure and function of the human central nervous system that develops from the neural tube made in vitro modeling quite challenging until the discovery of brain organoids. Human-induced pluripotent stem cells-derived brain organoids offer recapitulation of the features of early human neurodevelopment in vitro, including the generation, proliferation, and differentiation into mature neurons and micro-macroglial cells, as well as the complex interactions among these diverse cell types of the developing brain. Recent advancements in brain organoids, microfluidic systems, real-time sensing technologies, and their cutting-edge integrated use provide excellent models and tools for emulation of fundamental neurodevelopmental processes, the pathology of neurological disorders, personalized transplantation therapy, and high-throughput neurotoxicity testing by bridging the gap between two-dimensional models and the complex three-dimensional environment in vivo. In this review, we summarize how bioengineering approaches are applied to mitigate the limitations of brain organoids for biomedical and clinical research. We further provide an extensive overview and future perspectives of the humanized brain organoids-on-chip platforms with integrated sensors toward brain organoid intelligence and biocomputing studies. Such approaches might pave the way for increasing approvable clinical applications by solving their current limitations.

Keywords:  Biocomputing; Bioengineering; Brain organoids; Microfluidics; Organoid-on-a-chip; Sensors

DOI:  https://doi.org/10.1007/s00604-023-06165-4
Brain Commun. 2024 ;6(1): fcad331

Establishing mRNA and microRNA interactions driving disease heterogeneity in amyotrophic lateral sclerosis patient survival.

Rachel Waller, Joanna J Bury, Charlie Appleby-Mallinder, Matthew Wyles, George Loxley, Aditi Babel, Saleh Shekari, Mbombe Kazoka, Helen Wollff, Ammar Al-Chalabi, Paul R Heath, Pamela J Shaw, Janine Kirby.

  Amyotrophic lateral sclerosis is a fatal neurodegenerative disease, associated with the degeneration of both upper and lower motor neurons of the motor cortex, brainstem and spinal cord. Death in most patients results from respiratory failure within 3-4 years from symptom onset. However, due to disease heterogeneity some individuals survive only months from symptom onset while others live for several years. Identifying specific biomarkers that aid in establishing disease prognosis, particularly in terms of predicting disease progression, will help our understanding of amyotrophic lateral sclerosis pathophysiology and could be used to monitor a patient's response to drugs and therapeutic agents. Transcriptomic profiling technologies are continually evolving, enabling us to identify key gene changes in biological processes associated with disease. MicroRNAs are small non-coding RNAs typically associated with regulating gene expression, by degrading mRNA or reducing levels of gene expression. Being able to associate gene expression changes with corresponding microRNA changes would help to distinguish a more complex biomarker signature enabling us to address key challenges associated with complex diseases such as amyotrophic lateral sclerosis. The present study aimed to investigate the transcriptomic profile (mRNA and microRNA) of lymphoblastoid cell lines from amyotrophic lateral sclerosis patients to identify key signatures that are distinguishable in those patients who suffered a short disease duration (<12 months) (n = 22) compared with those that had a longer disease duration (>6 years) (n = 20). Transcriptional profiling of microRNA-mRNA interactions from lymphoblastoid cell lines in amyotrophic lateral sclerosis patients revealed differential expression of genes involved in cell cycle, DNA damage and RNA processing in patients with longer survival from disease onset compared with those with short survival. Understanding these particular microRNA-mRNA interactions and the pathways in which they are involved may help to distinguish potential therapeutic targets that could exert neuroprotective effects to prolong the life expectancy of amyotrophic lateral sclerosis patients.

Keywords:  amyotrophic lateral sclerosis; lymphoblastoid cell line; mRNA; miRNA; survival

DOI:  https://doi.org/10.1093/braincomms/fcad331
Mol Neurobiol. 2024 Jan 03.

Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples.

Sumit Kumar, Sidharth Mehan, Zuber Khan, Ghanshyam Das Gupta, Acharan S Narula.

  Amyotrophic lateral sclerosis (ALS) is a paralytic disease that damages the brain and spinal cord motor neurons. Several clinical and preclinical studies have found that methylmercury (MeHg+) causes ALS. In ALS, MeHg+-induced neurotoxicity manifests as oligodendrocyte destruction; myelin basic protein (MBP) deficiency leads to axonal death. ALS development has been connected to an increase in signal transducer and activator of transcription-3 (STAT-3), a mammalian target of rapamycin (mTOR), and a decrease in peroxisome proliferator-activated receptor (PPAR)-gamma. Guggulsterone (GST), a plant-derived chemical produced from Commiphorawhighitii resin, has been found to protect against ALS by modulating these signaling pathways. Vitamin D3 (VitD3) deficiency has been related to oligodendrocyte precursor cells (OPC) damage, demyelination, and white matter deterioration, which results in motor neuron death. As a result, the primary goal of this work was to investigate the therapeutic potential of GST by altering STAT-3, mTOR, and PPAR-gamma levels in a MeHg+-exposed experimental model of ALS in adult rats. The GST30 and 60 mg/kg oral treatments significantly improved the behavioral, motor, and cognitive dysfunctions and increased remyelination, as proven by the Luxol Fast Blue stain (LFB), and reduced neuroinflammation as measured by histological examinations. Furthermore, the co-administration of VitD3 exhibits moderate efficacy when administered in combination with GST60. Our results show that GST protects neurons by decreasing STAT-3 and mTOR levels while increasing PPAR-gamma protein levels in ALS rats.

Keywords:  Amyotrophic lateral sclerosis; JAK/STAT-3; Methylmercury; Neuroprotection; mTOR, PPAR-gamma, Demyelination, Oligodendrocytes

DOI:  https://doi.org/10.1007/s12035-023-03902-x
bioRxiv. 2023 Dec 17. pii: 2023.12.16.571979. [Epub ahead of print]

Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition.

Gabriel Talaia, Amanda Bentley-DeSousa, Shawn M Ferguson.

Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. At lysosomes, this TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.

DOI: https://doi.org/10.1101/2023.12.16.571979
Int J Biol Sci. 2024 ;20(1): 94-112

G3BP1 Interact with JAK2 mRNA to Promote the Malignant Progression of Nasopharyngeal Carcinoma via Activating JAK2/STAT3 Signaling Pathway.

Yuting Zhan, Weiyuan Wang, Haihua Wang, Yue Xu, Yuting Zhang, Yue Ning, Hongmei Zheng, Jiadi Luo, Yang Yang, Hongjing Zang, Ming Zhou, Songqing Fan.

  Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) is an RNA-binding protein implicated in various malignancies. However, its role in nasopharyngeal carcinoma (NPC) remains elusive. This study elucidates the potential regulation mechanisms of G3BP1 and its significance in NPC advancement. Through knockdown and overexpression approaches, we validate G3BP1's oncogenic role by promoting proliferation, migration, and invasion in vitro and in vivo. Moreover, G3BP1 emerges as a key regulator of the JAK2/STAT3 signaling pathway, augmenting JAK2 expression via mRNA binding. Notably, epigallocatechin gallate (EGCG), a green tea-derived antioxidant, counteracts G3BP1-mediated pathway activation. Clinical analysis reveals heightened G3BP1, JAK2, and p-STAT3 as powerful prognostic markers, with G3BP1's expression standing as an independent indicator of poorer outcomes for NPC patients. In conclusion, the study unveils the oncogenic prowess of G3BP1, its orchestration of the JAK2/STAT3 signaling pathway, and its pivotal role in NPC progression.

Keywords:  G3BP1; JAK2/STAT3 signaling pathway; RNA binding protein; malignant progression

DOI:  https://doi.org/10.7150/ijbs.85341
Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2306682120

Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera.

Yuquan Tong, Peiyuan Zhang, Xueyi Yang, Xiaohui Liu, Jie Zhang, Magda Grudniewska, Ikrak Jung, Daniel Abegg, Jun Liu, Jessica L Childs-Disney, Quentin M R Gibaut, Hafeez S Haniff, Alexander Adibekian, M Maral Mouradian, Matthew D Disney.

  α-Synuclein is an important drug target for the treatment of Parkinson's disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5' untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5' UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient-derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders.

Keywords:  Alzheimer’s; RNA; parkinsonism; targeted degradation; α-synuclein

DOI:  https://doi.org/10.1073/pnas.2306682120
Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2309700120

Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.

Liam D Aubrey, Natalia Ninkina, Sabine M Ulamec, Natalia Y Abramycheva, Eftychia Vasili, Oliver M Devine, Martin Wilkinson, Eilish Mackinnon, Galina Limorenko, Martin Walko, Sarah Muwanga, Leonardo Amadio, Owen M Peters, Sergey N Illarioshkin, Tiago F Outeiro, Neil A Ranson, David J Brockwell, Vladimir L Buchman, Sheena E Radford.

  α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.

Keywords:  ALS; aggregation; amyloid; oligomers; γ-synuclein

DOI:  https://doi.org/10.1073/pnas.2309700120
Nat Commun. 2024 Jan 02. 15(1): 145

Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis.

Yinan Yang, Huijing Zhou, Xiawei Huang, Chengfang Wu, Kewei Zheng, Jingrong Deng, Yonggang Zheng, Jiahui Wang, Xiaofeng Chi, Xianjue Ma, Huimin Pan, Rui Shen, Duojia Pan, Bo Liu.

The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals. We show that Tak1, a key kinase in innate immune/inflammatory signaling, activates the Hippo pathway by inducing the lysosomal degradation of Cka, an essential subunit of the STRIPAK PP2A complex that suppresses Hippo signaling. Suppression of STRIPAK results in the activation of Hippo pathway through Tao-Hpo signaling. We further show that Tak1-mediated Hippo signaling is involved in processes ranging from cell death to phagocytosis and innate immune memory. Our findings thus reveal a molecular connection between innate immune/inflammatory signaling and the evolutionally conserved Hippo pathway, thus contributing to our understanding of infectious, inflammatory and malignant diseases.

DOI: https://doi.org/10.1038/s41467-023-44542-y
bioRxiv. 2023 Dec 14. pii: 2023.11.13.566502. [Epub ahead of print]

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.

Estevão Scudese, Zer Vue, Prassana Katti, Andrea Marshall, Larry Vang, Edgar Garza López, Kit Neikirk, Dominique Stephens, Duane D Hall, Rahmati Rostami, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine Wanjalla, Aaron Whiteside, Clintoria Williams, Steven M Damo, Jennifer A Gaddy, Annet Kirabo, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Vernat Exil, Bret C Mobley, Antentor Hinton.

Sarcopenia is an age-related loss of skeletal muscle, characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although mitochondrial aging is associated with decreased mitochondrial capacity, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging still requires further elucidation. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern these changes remain unclear. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. We found that mitochondria became less complex with age. Specifically, mitochondria lost surface area, complexity, and perimeter, indicating age-related declines in ATP synthesis and interaction capacity. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), which we show is required for mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved with Marf, the MFN2 ortholog in Drosophila , as Marf knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusins.

DOI: https://doi.org/10.1101/2023.11.13.566502
ACS Chem Neurosci. 2024 Jan 02.

Phospholipids and Cholesterol Determine Molecular Mechanisms of Cytotoxicity of α-Synuclein Oligomers and Fibrils.

Kiryl Zhaliazka, Abid Ali, Dmitry Kurouski.

  Progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta, hypothalamus, and thalamus is a hallmark of Parkinson's disease. Neuronal death is linked to the abrupt aggregation of α-synuclein (α-Syn), a small membrane protein that regulates cell vesicle trafficking. α-Syn aggregation rate, as well as the secondary structure and toxicity of α-Syn fibrils, could be uniquely altered by lipids. However, molecular mechanisms that determine such a remarkable difference in the toxicity of α-Syn fibrils formed in the presence of lipids remain unclear. In this study, we used a set of molecular assays to determine the molecular mechanism by which α-Syn fibrils formed in the presence of phosphatidylcholine (PC), cardiolipin (CL), and cholesterol (Cho) exert cell toxicity. We found that rat dopaminergic cells exposed to α-Syn fibrils formed in the presence of different lipids exert drastically different magnitudes and dynamics of unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria (MT). Specifically, α-Syn:CL were found to cause the strongest, whereas α-Syn fibrils formed in the absence of lipids had the lowest magnitude of the UPR cell response. We also found the opposite dynamics of the ER- and MT-UPR responses in rat dopaminergic cells exposed to protein aggregates. These results could suggest that facing severe ER stress, dopaminergic cells suppress MT-UPR response, enabling the maximal ATP production to restore their normal physiological function. These findings help to better understand complex mechanisms of cell toxicity of amyloid aggregates and ultimately find neuroprotective drug candidates that will be able to suppress the spread of Parkinson's disease.

Keywords:  cardiolipin; cholesterol; mitochondria; phosphatidylcholine; unfolded protein response; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.3c00671
Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00117-4. [Epub ahead of print]75 101837

The biology of mitochondrial carrier homolog 2.

Xiaohe Zheng, Binxiang Chu.

  The mitochondrial carrier system is in charge of small molecule transport between the mitochondria and the cytoplasm as well as being an integral portion of the core mitochondrial function. One member of the mitochondrial carrier family of proteins, mitochondrial carrier homolog 2 (MTCH2), is characterized as a critical mitochondrial outer membrane protein insertase participating in mitochondrial homeostasis. Accumulating evidence demonstrate that MTCH2 is integrally linked to cell death and mitochondrial metabolism, and its genetic alterations cause a variety of disease phenotypes, ranging from obesity, Alzheimer's disease, and tumor. To provide a comprehensive insight into the current understanding of MTCH2, we present a detailed description of the physiopathological functions of MTCH2, ranging from apoptosis, mitochondrial dynamics, and metabolic homeostasis regulation. Moreover, we summarized the impact of MTCH2 in human diseases, and highlighted tumors, to assess the role of MTCH2 mutations or variable expression on pathogenesis and target therapeutic options.

Keywords:  Apoptosis; Lipid metabolism; MTCH2; Mitochondria; Tumor

DOI:  https://doi.org/10.1016/j.mito.2023.101837
BMC Biol. 2024 Jan 02. 22(1): 2

Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis.

Wei Jun Tan, Hannah R Hawley, Sarah J Wilson, Helen L Fitzsimons.

  BACKGROUND: Dysregulation of nucleocytoplasmic shuttling of histone deacetylase 4 (HDAC4) is associated with several neurodevelopmental and neurodegenerative disorders. Consequently, understanding the roles of nuclear and cytoplasmic HDAC4 along with the mechanisms that regulate nuclear entry and exit is an area of concerted effort. Efficient nuclear entry is dependent on binding of the transcription factor MEF2, as mutations in the MEF2 binding region result in cytoplasmic accumulation of HDAC4. It is well established that nuclear exit and cytoplasmic retention are dependent on 14-3-3-binding, and mutations that affect binding are widely used to induce nuclear accumulation of HDAC4. While regulation of HDAC4 shuttling is clearly important, there is a gap in understanding of how the nuclear and cytoplasmic distribution of HDAC4 impacts its function. Furthermore, it is unclear whether other features of the protein including the catalytic site, the MEF2-binding region and/or the ankyrin repeat binding motif influence the distribution and/or activity of HDAC4 in neurons. Since HDAC4 functions are conserved in Drosophila, and increased nuclear accumulation of HDAC4 also results in impaired neurodevelopment, we used Drosophila as a genetic model for investigation of HDAC4 function.RESULTS: Here we have generated a series of mutants for functional dissection of HDAC4 via in-depth examination of the resulting subcellular distribution and nuclear aggregation, and correlate these with developmental phenotypes resulting from their expression in well-established models of neuronal morphogenesis of the Drosophila mushroom body and eye. We found that in the mushroom body, forced sequestration of HDAC4 in the nucleus or the cytoplasm resulted in defects in axon morphogenesis. The actions of HDAC4 that resulted in impaired development were dependent on the MEF2 binding region, modulated by the ankyrin repeat binding motif, and largely independent of an intact catalytic site. In contrast, disruption to eye development was largely independent of MEF2 binding but mutation of the catalytic site significantly reduced the phenotype, indicating that HDAC4 acts in a neuronal-subtype-specific manner.
CONCLUSIONS: We found that the impairments to mushroom body and eye development resulting from nuclear accumulation of HDAC4 were exacerbated by mutation of the ankyrin repeat binding motif, whereas there was a differing requirement for the MEF2 binding site and an intact catalytic site. It will be of importance to determine the binding partners of HDAC4 in nuclear aggregates and in the cytoplasm of these tissues to further understand its mechanisms of action.

Keywords:  Ankyrin repeats; Brain; Drosophila; Eye; HDAC4; Histone deacetylase; MEF2; Mushroom body; Neuron; Photoreceptor

DOI:  https://doi.org/10.1186/s12915-023-01800-1
Nat Biotechnol. 2024 Jan 02.

Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.

Emiliano Hergenreder, Andrew P Minotti, Yana Zorina, Polina Oberst, Zeping Zhao, Hermany Munguba, Elizabeth L Calder, Arianna Baggiolini, Ryan M Walsh, Conor Liston, Joshua Levitz, Ralph Garippa, Shuibing Chen, Gabriele Ciceri, Lorenz Studer.

The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription. A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages.

DOI: https://doi.org/10.1038/s41587-023-02031-z
RNA Biol. 2024 Jan;21(1): 1-20

Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases.

Xiaqing Li, Yi Han, Yu Meng, Lianghong Yin.

  Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30-100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.

Keywords:  Exosome; Extracellular vesicle; diseases; miRNA; mitochondrial dysfunction

DOI:  https://doi.org/10.1080/15476286.2023.2293343
Nat Commun. 2024 Jan 04. 15(1): 205

VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity.

Ojasee Bapat, Tejas Purimetla, Sarah Kruessel, Monil Shah, Ruolin Fan, Christina Thum, Fiona Rupprecht, Julian D Langer, Vidhya Rangaraju.

Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.

DOI: https://doi.org/10.1038/s41467-023-44233-8