bims-proned 2025-04-27 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–04–27
eighteen papers selected by
Verena Kohler, Umeå University

Delineating the Mechanistic Insight of Inhibition of α-Synuclein Fibrillation by Neuro Metabolite, Myo-inositol: Implications in Synucleopathies-Related Disorders.
Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.
Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.
Structural-functional relevance of DNAJBs in protein aggregation and associated neurodegenerative diseases.
Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein.
Alpha-Synuclein drives NURR1 and NLRP3 Inflammasome dysregulation in Parkinson's disease: From pathogenesis to potential therapeutic strategies.
The interplay between α-synuclein aggregation and necroptosis in Parkinson's disease: a spatiotemporal perspective.
Zinc oxide nanoparticle interface moderation enhances the extent of α-synuclein sequestering against the protein amyloidosis.
HDCA alleviates Parkinson's disease symptoms by promoting autophagic degradation of α-synuclein in enteric neurons.
On Levodopa Interactions with Brain Disease Amyloidogenic Proteins at the Nanoscale.
Parkinson's disease and gut microbiota metabolites: The dual impact of vitamins and functional amyloids.
Kinetin mediated mutant huntingtin phosphorylation restores multiple dysregulated pathways in a cell line model of Huntington's disease.
Calcineurin-mediated regulation of growth-associated protein 43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration.
Application of modular isoxazoline-β2,2-amino acid-based peptidomimetics as chemical model systems for studying the tau misfolding.
Tau aggregation induces cell death in iPSC-derived neurons.
DEAD-Box Helicase 6 Blockade in Brain-Derived Aβ Oligomers From Alzheimer's Disease Patients Attenuates Neurotoxicity.
Neural-induced human adipose tissue-derived stem cell secretome exerts neuroprotection against rotenone-induced Parkinson's disease in rats.
Simply crushed zizyphi spinosi semen prevents neurodegenerative diseases and reverses age-related cognitive decline in mice.

ACS Chem Neurosci. 2025 Apr 21.

Delineating the Mechanistic Insight of Inhibition of α-Synuclein Fibrillation by Neuro Metabolite, Myo-inositol: Implications in Synucleopathies-Related Disorders.

Tanzeel Khan, Abdus Samad, Rashid Waseem, Ayesha Tazeen, Mohammad Shahid, Shama Parveen, Md Imtaiyaz Hassan, Asimul Islam.

  The fibrillation of α-synuclein (α-syn) is a major factor contributing to neuronal damage and is critical in developing synucleopathies-related disorders. Considering this, the discovery of new compounds that can inhibit or modulate α-syn aggregation is a significant area of research. While polyol osmolytes have been shown to reduce α-syn fibrillation, the impact of brain metabolites such as myo-inositol (MI) on α-syn aggregation has not yet been explored. This study is the first to examine the effects of MI on α-syn aggregation, utilizing spectroscopic, microscopic, and cell cytotoxicity assay. Various aggregation assays revealed that MI inhibits the α-syn fibrillation in a dose-dependent manner. Fluorescence microscopy observations suggest that MI inhibits the α-syn fibrillation by forming amorphous aggregates. MTT assay revealed that α-syn aggregates in the presence of different concentrations of MI were not toxic as compared to α-syn fibrils. Thus, the mechanistic insight of inhibition of α-syn fibrillation by MI was explored by employing interaction studies using spectroscopic, calorimetric, and in silico approaches. Surface plasmon resonance and isothermal titration calorimetry suggest that MI-α-syn interacted with significant binding affinity, and the reaction was spontaneous. Molecular docking results depict that MI interacted with the aggregation-prone residues (36-42) at the N-terminal of α-syn, thereby stabilizing the α-syn and preventing the fibril formation. Molecular dynamics simulation results demonstrate the stability of the complex formation of MI with α-syn. This study highlighted the mechanistic insight of MI on preventing the α-syn from forming amyloid fibril, which could be further explored for therapeutic management of synucleopathies-related disorders.

Keywords:  Brain osmolytes; Isothermal titration calorimetry; Surface plasmon resonance; Synucleopathies; α-Synuclein

DOI:  https://doi.org/10.1021/acschemneuro.4c00843
Nat Commun. 2025 Apr 23. 16(1): 3825

Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.

Ryan P McGlinchey, Sashary Ramos, Emilios K Dimitriadis, C Blake Wilson, Jennifer C Lee.

N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson's disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by intact mass spectrometry to lysosomal activity. To delineate essential charged residues in fibril formation, we selected an N-terminal truncation (66-140) that is generated solely from soluble α-syn by asparagine endopeptidase. Ala-substitutions at K80 and E83 impact aggregation kinetics, revealing their vital roles in defining fibril polymorphism. K80, E83, and K97 are identified to be critical for fibril elongation. Based on solid-state NMR, mutational and Raman studies, and molecular dynamics simulations, a E83-K97 salt bridge is proposed. Finally, participation of C-terminal Lys residues in the full-length α-syn fibril assembly process is also shown, highlighting that individual residues can be targeted for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-025-58899-9
Sci Adv. 2025 Apr 25. 11(17): eadq6077

Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons.

Laurent Guillaud, Anna Garanzini, Sarah Zakhia, Sandra De la Fuente, Dimitar Dimitrov, Susan Boerner, Marco Terenzio.

Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) condensed and underwent ATP-dependent liquid phase separation in vitro. Human inducible pluripotent stem cell-derived neurons from patients with PD and ALS displayed reduced axoplasmic fluidity and decreased intracellular ATP. Last, nicotinamide mononucleotide treatment successfully rescued intracellular ATP levels and axoplasmic viscosity in neurons from patients with PD and ALS and reduced TAR DNA-binding protein 43 (TDP-43) aggregation in human motor neurons derived from a patient with ALS. Thus, our data suggest that the hydrotropic activity of ATP contributes to the regulation of neuronal homeostasis under both physiological and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adq6077
Biochim Biophys Acta Proteins Proteom. 2025 Apr 18. pii: S1570-9639(25)00012-3. [Epub ahead of print]1873(4): 141074

Structural-functional relevance of DNAJBs in protein aggregation and associated neurodegenerative diseases.

Siraj Fatima, Priyanka Pandey, Sandeep K Sharma, Smriti Priya.

  DNAJ proteins, also known as HSP40s, are co-chaperones that regulate the multifunctionality of HSP70s in maintaining cellular protein homeostasis. The heterogeneous family of DNAJ co-chaperones is classified into three classes (A, B and C), where structural diversity within the class defines their specific functions. Among three classes, the DNAJB class of co-chaperones are associated with cellular compartment-specific protein folding, disaggregation and degradation of proteins and enables effective targeting of a broad spectrum of aggregation-prone substrate proteins. The structural divergence of DNAJBs is critical for regulating disaggregation and degradation functions through specific interactions with HSP70 and substrate proteins. While the role of DNAJBs in maintaining protein homeostasis is valuable in addressing protein aggregation in neurodegenerative diseases, a limited understanding of their mechanisms and cellular functions beyond co-chaperones restricts their therapeutic applications. In this review, the mechanism of DNAJBs regulating aggregation of pathogenic proteins such as α-synuclein, tau, amyloid-β, and huntingtin are discussed. Emphasis on the selectivity of DNAJBs towards folding, disaggregation and degradation functions of HSP70, substrate selection and involvement of different structural regions are explained to provide a structural and functional understanding of DNAJB proteins. Mutations in different DNAJBs linked with several proteins aggregation-related neuronal and neuromuscular diseases are discussed. The fundamental understanding of DNAJB diversity and functionality can assist future interventions for regulating protein homeostasis and managing associated diseases.

Keywords:  Co-chaperones; DNAJ; DNAJB; Molecular chaperones; Neurodegenerative diseases; Protein aggregation; Protein homeostasis

DOI:  https://doi.org/10.1016/j.bbapap.2025.141074
J Am Chem Soc. 2025 Apr 22.

Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein.

Yarra Venkatesh, Karthik B Narayan, Tobias Baumgart, E James Petersson.

Molecular rotor-based fluorophores (RBFs) that are target-selective and sensitive to both polarity and viscosity are valuable for diverse biological applications. Here, we have designed next-generation RBFs based on the underexplored bimane fluorophore either through a change in aryl substitution or varying π-linkages between the rotatable electron donors and acceptors to produce red-shifted fluorescence emissions with large Stokes shifts. RBFs exhibit a twisted intramolecular charge transfer mechanism that enables control of polarity and viscosity sensitivity as well as target selectivity. These features enable their application in (1) turn-on fluorescent detection of α-synuclein (αS) fibrils, a hallmark of Parkinson's disease, including amplified fibrils from patient samples; (2) monitoring early misfolding and oligomer formation during αS aggregation; and (3) selective imaging of αS condensates formed by liquid-liquid phase separation. In all three cases, we show that our probes have high levels of selectivity for αS compared to other aggregating proteins. These properties enable one to study the interplay of αS and tau in amyloid aggregation and the mechanisms underlying neurodegenerative disorders.

DOI: https://doi.org/10.1021/jacs.4c17933
Int Immunopharmacol. 2025 Apr 22. pii: S1567-5769(25)00682-4. [Epub ahead of print]156 114692

Alpha-Synuclein drives NURR1 and NLRP3 Inflammasome dysregulation in Parkinson's disease: From pathogenesis to potential therapeutic strategies.

Ahmed M Abdelaziz.

  Parkinson's disease (PD), a progressive neurodegenerative disorder, is characterized by the loss of dopaminergic neurons and pathological aggregation of α-synuclein (α-Syn). Emerging evidence highlights the interplay between genetic susceptibility, neuroinflammation, and transcriptional dysregulation in driving PD pathogenesis. This review brings together the latest information on three important players: α-Syn, the transcription factor Orphan nuclear receptor (NURR1), and the NOD-like receptor 3 (NLRP3) inflammasome. Pathogenic α-syn aggregates cause damage to neurons by disrupting mitochondria and lysosomes and spreading in a way similar to prion proteins. They also turn on the NLRP3 inflammasome, which is a key player in neuroinflammation. NLRP3-driven release of pro-inflammatory cytokines exacerbates neurodegeneration and creates a self-sustaining inflammatory milieu. Meanwhile, reduced NURR1 activity, a pivotal modulator of dopaminergic neuron survival and development, exposes neurons to oxidative stress, neuroinflammation, and α-Syn toxicity, hence exacerbating disease progression. So, targeting this trio exhibits transformative potential against PD pathogenesis.

Keywords:  NLRP3 inflammasome; NURR1; Neurodegeneration; Parkinson's disease; Therapeutic targets; Α-Synuclein

DOI:  https://doi.org/10.1016/j.intimp.2025.114692
Front Neurosci. 2025 ;19 1567445

The interplay between α-synuclein aggregation and necroptosis in Parkinson's disease: a spatiotemporal perspective.

Haoran Xiang.

  Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the death of dopaminergic neurons and the aggregation of alpha-synuclein (α-Syn). It presents with prominent motor symptoms, and by the time of diagnosis, a significant number of neurons have already been lost. Current medications can only alleviate symptoms but cannot halt disease progression. Studies have confirmed that both dopaminergic neuronal loss and α-Syn aggregation are associated with necroptosis mechanisms. Necroptosis, a regulated form of cell death, has been recognized as an underexplored hotspot in PD pathogenesis research. In this review, we propose a spatiotemporal model of PD progression, highlighting the interactions between α-Syn aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation and necroptosis. These processes not only drive motor symptoms but also contribute to early non-motor symptoms, offering insights into potential diagnostic markers. Finally, we touch upon the therapeutic potential of necroptosis inhibition in enhancing current PD treatments, such as L-Dopa. This review aims to provide a new perspective on the pathogenesis of PD and to identify avenues for the development of more effective therapeutic strategies.

Keywords:  Parkinson’s disease; alpha-synuclein; mitochondrial dysfunction; necroptosis; neuroinflammation; oxidative stress; therapeutic strategies

DOI:  https://doi.org/10.3389/fnins.2025.1567445
Int J Biol Macromol. 2025 Apr 18. pii: S0141-8130(25)03696-7. [Epub ahead of print]310(Pt 2): 143144

Zinc oxide nanoparticle interface moderation enhances the extent of α-synuclein sequestering against the protein amyloidosis.

Sonali Mohanty, Dipita Bhattacharyya, Ajit Kumar Singh, Amaresh Mahakud, Sonali Jena, Harshit Kalra, Mohammed Saleem, Anupam Nath Jha, Anirban Bhunia, Suman Jha.

  Parkinson's disease is a progressive neurodegenerative disorder that is often associated with plaque deposition, known as Lewy Bodies. Lewy Bodies are predominantly composed of α-synuclein amyloid fibrils. α-Synuclein is a soluble intrinsically disordered protein (IDP) with proposed multiple physiological functions, consisting of aggregation-prone non-amyloid β component (NAC) region in its sequence. Amyloid aggregation of α-synuclein goes through a cytotoxic intermediate(s), leading to structurally mature cross-β sheet-rich fibrils as its end product. Metal nanoparticles with a biocompatible nature have been adopted for different biological applications. Thus, sequestering of α-synuclein monomer onto the metal nanoparticle will potentially impede Parkinson's onset/progression. In this study, interaction of α-synuclein with zinc oxide nanoparticle (ZnONP) having positive surface potential, and moderated ZnONP with negative surface-functional group(s), were explored. The interaction studies indicate that the NAC region interacts with the nanoparticle to sequester the monomeric protein into an amorphous aggregate, thus extending the lag phase of protein fibrillation. Interestingly, α-synuclein complexed with ZnONP exhibits remarkably lowered cytotoxicity against the SH-SY5Y cell in-vitro, compared to the treatment with only ZnONP interfaces or α-synuclein fibrils.

Keywords:  Amyloid; Nano-bio interfacial interaction; Nanoparticle; Parkinson's disease; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143144
Phytomedicine. 2025 Apr 12. pii: S0944-7113(25)00388-5. [Epub ahead of print]142 156749

HDCA alleviates Parkinson's disease symptoms by promoting autophagic degradation of α-synuclein in enteric neurons.

Ren-Yu Kong, Jin-Bao Zhang, Xu Miao, Xiao-Yu Yao, Mei-Hua Pan, Xin Yin, Rui-Qin Yao, Chao Ren.

   INTRODUCTION: Bile acids (BAs) are emerging as key modulators of Parkinson's disease (PD) through gut-brain interactions, yet their therapeutic potential remains underutilized. While BA imbalances contribute to PD pathogenesis, the specific subspecies regulating α-synuclein (α-syn) homeostasis and their mechanisms in enteric neurons-critical sites for PD initiation-require systematic investigation.
OBJECTIVE: To investigate whether hyodeoxycholic acid (HDCA), a secondary BA with documented neuroprotective properties but unproven efficacy in synucleinopathy, modulates α-syn clearance through enteric neuronal autophagy to mitigate PD progression.
METHODS: A53T transgenic mice underwent behavioral assessments for PD phenotyping. State-of-the-art UPLC/MS-based metabolomics quantified BA profiles. Pharmacological interventions using target-specific inhibitors (Gly-MCA, T0070907, VER-155,008) dissected the FXR-PPARγ-HSPA8 pathway. Multiscale analyses spanning immunofluorescence, western blotting, and LC3B autophagy flux reporter assays elucidated α-syn aggregation and autophagic dynamics in primary enteric neurons.
RESULTS: HDCA decline correlated with PD severity, positioning it as a novel biomarker for gut-brain axis dysfunction in PD. HDCA supplementation not only alleviated motor/non-motor deficits but also conferred dual neuroprotection-reducing colonic α-syn oligomers and preserving nigral dopaminergic neurons. Mechanistic decoding revealed HDCA's unparalleled capacity to activate enteric neuronal autophagy via FXR-PPARγ-HSPA8 signaling, a pathway previously unrecognized in PD therapeutics.
CONCLUSION: Our study reveals a novel gut-brain axis where HDCA depletion drives PD pathogenesis via FXR-PPARγ-HSPA8-mediated autophagic dysfunction in enteric neurons. PD-associated HDCA deficiency directly impairs α-syn clearance, identifying HDCA as both a gut-derived synucleinopathy biomarker and a therapeutic target.

Keywords:  Alpha-synuclein; Autophagy; Heat shock protein 8; Hyodeoxycholic acid; PPARγ; Parkinson's disease

DOI:  https://doi.org/10.1016/j.phymed.2025.156749
ACS Omega. 2025 Apr 15. 10(14): 14487-14495

On Levodopa Interactions with Brain Disease Amyloidogenic Proteins at the Nanoscale.

Talia Bergaglio, Nico Kummer, Shayon Bhattacharya, Damien Thompson, Silvia Campioni, Peter Niraj Nirmalraj.

The cerebral accumulation of α-synuclein (α-Syn) and amyloid β-1-42 (Aβ-42) proteins is known to play a key role in the pathology of Parkinson's disease (PD). Currently, levodopa (L-dopa) is the first-line dopamine replacement therapy for treating bradykinetic symptoms (i.e., difficulty initiating physical movements), which become visible in PD patients. Using atomic force microscopy, we evidence at nanometer length scales the differential effects of L-dopa on the morphology of α-Syn and Aβ-42 protein fibrils. L-dopa treatment was observed to reduce the length and diameter of both types of protein fibrils, with a stark reduction mainly observed for Aβ-42 fibrils in physiological buffer solution and human cerebrospinal fluid. The insights gained on Aβ-42 fibril disassembly from the label-free nanoscale imaging experiments are substantiated by using atomic-scale molecular dynamics simulations. Our results indicate L-dopa-driven reversal of amyloidogenic protein aggregation, which might provide leads for designing chemical effector-mediated disassembly of insoluble protein aggregates.

DOI: https://doi.org/10.1021/acsomega.5c01028
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 18. pii: S0925-4439(25)00210-8. [Epub ahead of print] 167862

Parkinson's disease and gut microbiota metabolites: The dual impact of vitamins and functional amyloids.

Fatemeh Mirab, Mitra Pirhaghi, Daniel E Otzen, Ali Akbar Saboury.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal accumulation of alpha-synuclein (α-Syn). Recent research emphasizes the significant role of the gut microbiota, the diverse community of microbes living in the intestines, in modulating α-Syn pathology. This review explores the bi-directional communication along the microbiota-gut-brain axis, highlighting the paradoxical impact of two gut microbiota metabolites-functional bacterial amyloids (FuBA) and vitamins-on neurodegenerative diseases, particularly PD. FuBA contributes to PD pathogenesis by promoting α-Syn aggregation, while vitamins offer neuroprotection through their anti-amyloidogenic, antioxidant, and anti-inflammatory properties. Understanding these processes could lead to precision clinical approaches and novel strategies for managing and preventing PD.

Keywords:  Functional bacterial amyloids; Gut microbiota; Parkinson's disease; Vitamin; α-Synuclein

DOI:  https://doi.org/10.1016/j.bbadis.2025.167862
Hum Mol Genet. 2025 Apr 23. pii: ddaf052. [Epub ahead of print]

Kinetin mediated mutant huntingtin phosphorylation restores multiple dysregulated pathways in a cell line model of Huntington's disease.

Rajubhai Dabhi, Ragi Mehta, Dhruvi Kakadiya, Ravi Vijayvargia.

  Huntington's disease (HD) is a fatal neurodegenerative disease caused by CAG trinucleotide repeat expansion in the huntingtin gene (Htt) resulting in an expanded polyglutamine (polyQ) tract in the huntingtin (HTT) protein. The expanded polyQ alters structure of HTT making it susceptible to aggregation. The expression of mutant HTT (mHTT) causes dysregulation of several key cellular pathways in neuronal cells resulting in neurodegeneration. Recent studies have demonstrated phosphorylation of the N-terminal domain of the huntingtin (N-HTT) protein as an important regulator of its localization, structure, aggregation, clearance and toxicity. Most studies have focused on the effect of phosphorylation of Ser13 and Ser16 in N-HTT on protein aggregation and reported a drastic reduction in aggregation. However, the downstream impact of this phosphorylation status on key cellular pathways is largely unexplored. Utilizing an inducible cell line model for expression of Exon 1 fragment of mHTT bearing 150 polyglutamine repeats (HD150Q), we demonstrate that kinetin induced phosphorylation at Ser13 and Ser16 of N-HTT resulted in prevention of aggregation as well as resolution of preformed aggregates. Furthermore, kinetin treatment led to rescue of ATP levels and transcription of key genes as well as significant reduction in mitochondrial ROS levels restoring mitochondrial function. Notably, ER stress markers were significantly reduced at transcriptional, translational and post-translational levels. Restoration of mitochondrial function and mitigation of ER stress lead to significant improvement in cell survival. These findings further strengthen the view that HTT N-terminal phosphorylation is a promising therapeutic target for HD.

Keywords:  Huntingtin phosphorylation; Huntington’s disease; Kinetin; Mutant huntingtin

DOI:  https://doi.org/10.1093/hmg/ddaf052
Front Aging Neurosci. 2025 ;17 1566465

Calcineurin-mediated regulation of growth-associated protein 43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration.

Ekaterina Grebenik, Sofia Zaichick, Gabriela Caraveo.

   Introduction: Elevated calcium (Ca2+) levels and hyperactivation of the Ca2+-dependent phosphatase calcineurin are key factors in α-synuclein (α-syn) pathobiology in Dementia with Lewy Bodies and Parkinson's Disease (PD). Calcineurin activity can be inhibited by FK506, an FDA-approved compound. Our previous work demonstrated that sub-saturating doses of FK506 provide neuroprotection against α-syn pathology in a rat model of α-syn neurodegeneration, an effect associated with the phosphorylation of growth-associated protein 43 (GAP-43).
Methods: To investigate the role of GAP-43 phosphorylation, we generated phosphomutants at the calcineurin-sensitive sites and expressed them in PC12 cells and primary rat cortical neuronal cultures to assess their effects on neurite morphology and synapse formation. Additionally, we performed immunoprecipitation mass spectrometry in HeLa cells to identify binding partners of these phosphorylation sites. Finally, we evaluated the ability of these phosphomutants to modulate α-syn toxicity.
Results: In this study, we demonstrate that calcineurin-regulated phosphorylation at S86 and T172 of GAP-43 is a crucial determinant of neurite branching and synapse formation. A phosphomimetic GAP-43 mutant at these sites enhances both processes and provides protection against α-syn-induced neurodegeneration. Conversely, the phosphoablative mutant prevents neurite branching and synapse formation while exhibiting increased interactions with ribosomal proteins.
Discussion: Our findings reveal a novel mechanism by which GAP-43 activity is regulated through phosphorylation at calcineurin-sensitive sites. These findings suggest that FK506's neuroprotective effects may be partially mediated through GAP-43 phosphorylation, providing a potential target for therapeutic intervention in synucleinopathies.

Keywords:  FK506; GAP-43; calcineurin; neurite branching; neuroprotection; synapses; α-synuclein

DOI:  https://doi.org/10.3389/fnagi.2025.1566465
iScience. 2025 Apr 18. 28(4): 112272

Application of modular isoxazoline-β2,2-amino acid-based peptidomimetics as chemical model systems for studying the tau misfolding.

Davide di Lorenzo, Nicolo Bisi, Raffaella Bucci, Inga Ennen, Leonardo Lo Presti, Veronica Dodero, Roland Brandt, Sandrine Ongeri, Maria-Luisa Gelmi, Nicolo Tonali.

  Tau is a microtubule-associated protein essential for regulating microtubule dynamics and axonal transport in neurons. In tauopathies, the transition of tau from a physiological to a pathological form remains unclear, though the hexapeptides PHF6 and PHF6∗ are key in triggering aggregation. These sequences are shielded by a β-hairpin structure in the native state but expose hydrophobic residues during misfolding, promoting self-assembly. This study employs a non-natural β2-amino acid to induce PHF6 and PHF6∗ into either extended or β-hairpin conformations. The extended form triggers tau aggregation without additives, acting as a seed-competent monomer model system. Conversely, the β-hairpin preserves tau in a soluble monomeric state. Additionally, a β-hairpin mimic inspired by Hsp90 showed potential as a chaperone mimic and inhibitor of tau aggregation, offering insights into corrective folding and aggregation modulation in neuronal environments.

Keywords:  Biochemistry; Molecular biology; Structural biology

DOI:  https://doi.org/10.1016/j.isci.2025.112272
Aging Brain. 2025 ;7 100136

Tau aggregation induces cell death in iPSC-derived neurons.

Hirokazu Tanabe, Sumihiro Maeda, Etsuko Sano, Norio Sakai, Setsu Endoh-Yamagami, Hideyuki Okano.

  Abnormal accumulation of tau proteins in the brain is a hallmark of neurodegenerative diseases such as Alzheimer's disease and is closely linked with neuronal cell death. Tau accumulation is a prominent therapeutic target for Alzheimer's disease, since tau accumulation correlates well with the disease progression, and tau-targeting drugs hold potentials to halt the disease progression. Given the differential response of human and mouse neuronal cells, there is a critical need for a human cellular platform to quickly screen for tau-related neurodegenerative disease therapeutics. However, inducing rapid, tau-dependent neuronal cell death in human models remains challenging. In this study, we established a human cellular model capable of inducing tau aggregation-dependent neuronal cell death within two weeks via tau overexpression. Additionally, we demonstrated the neuroprotective efficacy of known tau-targeting compounds within this system. These findings suggest that our cellular model recapitulates the molecular pathogenesis of tau-induced neurodegeneration and could serve as a valuable platform for drug screening in tauopathies.

Keywords:  Aggregation; Neuronal cell death; Overexpression; Tau; iPSC

DOI:  https://doi.org/10.1016/j.nbas.2025.100136
MedComm (2020). 2025 May;6(5): e70156

DEAD-Box Helicase 6 Blockade in Brain-Derived Aβ Oligomers From Alzheimer's Disease Patients Attenuates Neurotoxicity.

Xiaoxu Wang, Lu Dai, Na Wu, Donghui Wu, Xinyuan Wang, Xia Meng, Qilei Zhang, Jing Lu, Xiaoxin Yan, Jing Zhang, Baian Chen.

  There are no effective curative treatments for Alzheimer's disease (AD), the most prevalent form of dementia. Amyloid-beta (Aβ) oligomers are considered key neurotoxic molecules that trigger AD. Recent studies have shown that direct antibody targeting of Aβ oligomers is beneficial for early AD patients; however, serious side effects (e.g., brain hemorrhage, edema, and shrinkage) persist. Considering that Aβ oligomers readily bind to other proteins, contributing to neurotoxicity and AD onset, those proteins could represent alternative therapeutic targets. However, proteins that bind to Aβ oligomers in the brains of AD patients have not yet been identified. In this study, we identified four proteins (DDX6, DSP, JUP, and HRNR) that bind to Aβ oligomers derived from the brains of AD patients. Intriguingly, among these four proteins, only the blockade of DEAD-box helicase 6 (DDX6) in human-derived Aβ oligomers attenuated their neurotoxicity both in vitro and in vivo. Mechanistic analysis revealed that DDX6 promotes the formation of Aβ oligomers, likely due to DDX6 bind to Aβ oligomers at four distinct sites. These findings suggest that DDX6 could serve as a potential therapeutic target to reduce the neurotoxicity of Aβ oligomers in the brain and prevent the progression of AD.

Keywords:  Alzheimer's disease; Aβ oligomers; DDX6; neurotoxicity

DOI:  https://doi.org/10.1002/mco2.70156
Stem Cell Res Ther. 2025 Apr 20. 16(1): 193

Neural-induced human adipose tissue-derived stem cell secretome exerts neuroprotection against rotenone-induced Parkinson's disease in rats.

Mahesh Ramalingam, Sujeong Jang, Jinsu Hwang, Hyong-Ho Cho, Byeong C Kim, Han-Seong Jeong.

   BACKGROUND: Parkinson's disease (PD) is a multifactorial disease that involves genetic and environmental factors, which play an essential role in the pathogenesis of PD. Mesenchymal stem cells release a set of bioactive molecules called "secretome" that regulates intercellular communication and cargo transfer in signaling pathways for PD treatment. Thus, this study aimed to evaluate the neuroprotective effects of neural-induced human adipose tissue-derived stem cell (NI-hADSC)-conditioned medium (NI-hADSC-CM) and its exosomes (NI-hADSC-Exo) in a rotenone (ROT)-induced model of PD in rats.
METHODS: The NI-hADSC-CM was collected from NI-hADSC after 14 days of neural differentiation, and its NI-hADSC-Exo were isolated using a tangential flow filtration system. ROT (1 mg/kg) was subcutaneously administered for 28 days to establish a model of PD in rats. The treatment of NI-hADSC-CM or NI-hADSC-Exo was intravenously injected on days 15, 18, 21, 24, and 27. Animal behavioral effects were explored via a rotarod test. After 28 days, histological and western blot analyses were performed to investigate the tyrosine hydroxylase (TH), α-synuclein (α-syn) aggregation, and downstream signaling pathways for experimental validation.
RESULTS: NI-hADSC-Exo improved the motor balance and coordination skills against ROT toxicity. ROT reproduced the pathological features of PD, such as a decrease in TH-positive dopaminergic neurons and an increase in α-syn aggregation and glial fibrillary acidic protein (GFAP)-positive cells. NI-hADSC-CM and NI-hADSC-Exo improved the TH expression, decreased the Triton X-100 soluble and insoluble oligomeric p-S129 α-syn, and influenced the differential reactivity to astrocytes and microglia. Secretome treatment could reverse the ROT-induced damages in the neuronal structural and functional proteins, mitochondrial apoptosis, and caspase cascade. The treatment of NI-hADSC-CM and NI-hADSC-Exo ameliorated the ROT toxicity-induced serine-threonine protein kinase dysregulation and autophagy impairment to clear the aggregated α-syn.
CONCLUSIONS: NI-hADSC-CM and NI-hADSC-Exo significantly exerted neuroprotection by decreasing α-syn toxicity, inhibiting neuroinflammation and apoptosis, restoring autophagic flux properties, and promoting the neuronal function in ROT-injected rats; however, the influence of these treatments on signaling pathways differed slightly between the midbrain and striatum regions. Targeting α-syn degradation pathways provides a novel strategy to elucidate the beneficial effects of MSC secretome and future safe cell-free treatments for PD.

Keywords:  Alpha-synuclein; Autophagy; Exosomes; Neuronal markers; Protein kinases

DOI:  https://doi.org/10.1186/s13287-025-04306-5
Elife. 2025 Apr 23. pii: RP100737. [Epub ahead of print]13

Simply crushed zizyphi spinosi semen prevents neurodegenerative diseases and reverses age-related cognitive decline in mice.

Tomohiro Umeda, Ayumi Sakai, Rumi Uekado, Keiko Shigemori, Ryota Nakajima, Kei Yamana, Takami Tomiyama.

  Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer's disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson's disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.

Keywords:  aging; dementia; medicine; mouse; neurodegenerative disease; neuroscience; rejuvenation; senescence; traditional Chinese medicine

DOI:  https://doi.org/10.7554/eLife.100737