bims-proned 2026-04-19 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–04–19
twelve papers selected by
Verena Kohler, Umeå University

WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.
Alpha synuclein variants significantly influence the propensity for clustering and pore formation in giant unilamellar vesicles.
Nuclear export modulates TDP-43 phase transitions and cytoplasmic aggregation.
A metabolite extracted from E. coli suppresses tau aggregation.
The aggregation of amyloid-β: from condensation, nucleation, and conformation to targeting therapy.
Disruption of Synaptic Vesicle Trafficking in Alzheimer's and Parkinson's Disease: Mechanisms and Therapeutic Implication.
Nano-plasmonic SERS-based serum fingerprinting for analytical monitoring of Parkinson's disease and therapeutic response.
An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.
Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.
Impaired autophagy from TRPV4 activation drives α-synuclein pathology in a Parkinson's disease model: A toxicological insight.
Transient Aggregation-Prone States in Disordered Proteins as Therapeutic Targets: The Amyloid-β Case.
Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

bioRxiv. 2026 Apr 07. pii: 2026.04.03.716340. [Epub ahead of print]

WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.

Maxime Teixeira, Razan Sheta, Morgan Bérard, Christine Insinna, Anne-Laure Mahul-Mellier, Constantin V L Delmas, Eva Lépinay, Walid Idi, Alexandra Ricard, Esther Del Cid-Pellitero, Christine Trabolsi, Stéphane Gobeil, Marie-Hélène Canron, Erwan Bézard, Alex Rajput, Francesca Cicchetti, Martin Parent, Edward A Fon, Nagendran Ramalingam, Ulf Dettmer, Frederic Calon, Christopher Westlake, Hilal A Lashuel, Abid Oueslati.

The aggregation of α-synuclein (α-SYN) into Lewy bodies (LBs) is a central event in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies 1,2 . Despite significant advances in understanding α-SYN self-assembly, the precise sequence of early aggregation steps has not been directly visualized in living neurons. Here, we use an optogenetic-induced protein aggregation system with a high temporal resolution to monitor the onset of α-SYN assembly in neurons. We found that the initiation and accumulation of α-SYN aggregates occur predominantly at the lysosomal membrane, an event driven by the α-SYN N-terminus and modulated by the membrane-associated adaptor protein WD repeat-containing protein 44 (WDR44). Remarkably, we demonstrate that WDR44 knockdown markedly reduced de novo α-SYN aggregation in both neuronal cultures and in vivo, whereas WDR44 overexpression enhances α-SYN aggregation in PD patient-derived iPSC neurons. Consistent with its potential pathogenic involvement, WDR44 aberrantly accumulates in vivo and in the brains of PD patients, where it colocalizes with LB inclusions. Finally, we show that lysosome-associated α-SYN aggregates compromised lysosomal structure and function, leading to neuronal impairment, a phenotype worsened by WDR44 overexpression, linking early aggregation events to downstream toxicity. Together, these findings reveal the earliest dynamic stages of α-SYN oligomerization in living neurons and identify the WDR44-α-SYN interaction as a promising therapeutic target for reducing α-SYN pathology and enabling early intervention in PD.

DOI: https://doi.org/10.64898/2026.04.03.716340
Biochim Biophys Acta Biomembr. 2026 Apr 14. pii: S0005-2736(26)00035-0. [Epub ahead of print] 184532

Alpha synuclein variants significantly influence the propensity for clustering and pore formation in giant unilamellar vesicles.

Surajit Das, Rajeev Jain, Krishnananda Chattopadhyay, Sanat Karmakar.

  Alpha-synuclein (α-syn), a presynaptic neuronal protein, is believed to play significant roles in Parkinson's disease (PD), the second most common neurodegenerative disorder. An aberrant aggregation of fibrillar form within Lewy bodies is the main neuropathological characteristic of PD. The interaction of α-syn with cellular membranes, as well as binding of α-syn to these membranes is crucial in the process of accumulations. In this study, we explored the aggregation behaviour of α-syn in both its monomeric and fibrillar forms when exposed to giant unilamellar vesicles (GUVs) composed of DOPC-cholesterol (10 mol%). We also investigated N-terminal (ΔN) and C-terminal (ΔC) truncated variants of α-syn to better understand the role of these end terminal regions on vesicle clustering and pore formation in GUVs. Both the full-length and ΔC forms of α-syn, whether in monomeric or fibrillar states, exhibited vesicle clustering. In contrast, the ΔN variant exhibited behaviour akin to a system devoid of α-syn, underscoring its critical role in mediating the interaction of α-syn with the membrane. In addition to vesicle clustering, we also observed membrane leakage induced by both the ΔC and full chain conformations of α-syn. The permeation rate of GUVs in the presence of monomeric α-syn was found to be higher than that associated with the fibrillar form of α-syn. Our research suggests that the variant of α-syn inhibits vesicle clustering and shows the least impact on permeation kinetics, thereby offering a potential strategy to understand the pathophysiology associated with PD.

Keywords:  Alpha-synuclein (-syn); Giant unilamellar vesicles; Model membrane; Parkinson's disease; Phase contrast microscopy; Protein aggregation

DOI:  https://doi.org/10.1016/j.bbamem.2026.184532
bioRxiv. 2026 Apr 12. pii: 2025.12.16.694670. [Epub ahead of print]

Nuclear export modulates TDP-43 phase transitions and cytoplasmic aggregation.

Natalie Chin, Qi Zhang, Jizhong Zou, Ken Chih-Chien Cheng, Wei Zheng, Yihong Ye.

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase behavior may influence its aggregation propensity and neurotoxic activity. The mechanism(s) that modulates the transition of TDP-43 from a liquid to solid phase is poorly defined. Here we combine chemical and genome-wide genetic screenings to identify cellular factors that modulate the phase behavior of an RNA-binding defective TDP-43 mutant that mimics an Amyotrophic Lateral Sclerosis (ALS)-associated variant. Our screens uncover multiple cellular processes including RNA splicing, protein translation, proteostasis imbalance and nuclear export as TDP-43 phase regulators. Importantly, TDP-43 phase transition can be dynamically recapitulated in vitro in a semi-permeabilized cell system, which reveals that the inhibition of nuclear export reshapes the nuclear environment in favor of an RNA-dependent TDP-43 liquid-liquid phase separation (LLPS) state, which mitigates cytoplasmic TDP-43 aggregation. We validated this mechanism in a brain organoid model bearing an ALS-associated mutation, showing that nuclear export deficiency can limit pathogenic phospho-TDP-43 accumulation. These findings establish nuclear export as a key regulator of TDP-43 phase transitions and define a mechanistic framework that links altered nuclear transport and phase dynamics to TDP-43 aggregation potential.

DOI: https://doi.org/10.64898/2025.12.16.694670
Biochem J. 2026 Apr 15. pii: BCJ20260068. [Epub ahead of print]

A metabolite extracted from E. coli suppresses tau aggregation.

Mahalashmi Srinivasan, Akhil Patel, Tark Patel, Jack Moore, Erik Gomez-Cardona, Allan Yarahmady, Brian D Sykes, Olivier Julien, Sue-Ann Mok.

  Tau aggregation is a key pathological feature of neurodegenerative diseases termed tauopathies. Identifying the various cellular factors that function to prevent tau aggregation in cells can generate key insights into how to mitigate diseases associated with protein misfolding. During an investigation into developing purification methods for the protein tau, we observed that isolates of E. coli style lysate prevented human tau aggregation in vitro. Fractionation of the lysate was used to further isolate a small molecular weight (MW) inhibitory fraction containing multiple components, as determined by mass spectrometry and NMR. A putative inhibitory component, methylphosphonic acid (MePn), decreased tau amyloid formation when supplemented to in vitro style aggregation assays. MePn also blocked the aggregation of expressed tau in live E. coli when supplemented to the culture media. Our findings can be directly applied to optimizing purification of recombinant tau protein and more broadly, highlight the potential of cellular metabolites to directly modulate tau amyloid formation.

Keywords:  Escherichia coli; amyloid; protein aggregation; protein purification; tau proteins

DOI:  https://doi.org/10.1042/BCJ20260068
Life Sci. 2026 Apr 15. pii: S0024-3205(26)00206-7. [Epub ahead of print] 124397

The aggregation of amyloid-β: from condensation, nucleation, and conformation to targeting therapy.

Bangyao Chen, Tiancheng Chen, Zhendong Sun, Lulu Liu, Yu Jia, Yipin Ji, Jinlong Wang, Feifei Sun, Yunpeng Huang.

  Senile plaques consist of Amyloid-β (Aβ) are the pathological hallmark of Alzheimer's disease (AD), which is the most common type of neurodegenerative disorder. Aβ is a small peptide that consists of 38 to 43 amino acids. It causes harmful effects through abnormal aggregation, like the formation of oligomers and protofibrils. These aggregates can disrupt normal synaptic function and trigger a series of neuroinflammatory and neurodegenerative changes. The aggregation dynamics of Aβ are modulated by multiple factors, such as conformational transitions, the exposure of hydrophobic segments, liquid-liquid phase separation, and post-translational modifications. These factors can promote the formation of diverse aggregates with distinct conformations. This review summarizes the structural characteristics of various Aβ aggregates, along with related regulatory elements, their effects on cellular processes, and therapeutic strategies targeting Aβ and its aggregates. This overview contributes to a better understanding of the complex mechanisms underlying Aβ aggregation and its pathological consequences, as well as the basis for future therapies targeted to Aβ and aggregates.

Keywords:  Alzheimer's disease; Aβ aggregation; Aβ nucleation; Aβ toxicity; Aβ-targeting therapy

DOI:  https://doi.org/10.1016/j.lfs.2026.124397
Int J Mol Sci. 2026 Mar 28. pii: 3089. [Epub ahead of print]27(7):

Disruption of Synaptic Vesicle Trafficking in Alzheimer's and Parkinson's Disease: Mechanisms and Therapeutic Implication.

Youyang Zhu, Lianna Zhao, Yingming Li, Miao Tian, Yingdi Liao, Jinqing Huang, Peixin Guo, Yuhuan Xie.

  Alzheimer's (AD) and Parkinson's disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca2+-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions.

Keywords:  Alzheimer’s disease; Parkinson’s disease; SNARE complex; protein aggregation; synaptic vesicle trafficking

DOI:  https://doi.org/10.3390/ijms27073089
Mikrochim Acta. 2026 Apr 15. pii: 318. [Epub ahead of print]193(5):

Nano-plasmonic SERS-based serum fingerprinting for analytical monitoring of Parkinson's disease and therapeutic response.

Monalisha Nayak, Ashish Kumar Singh, Ranjan Kumar Singh.



Keywords:  Nano-bio interfaces; Nano-plasmonic silver nanoparticles; Neurodegenerative disease biomarkers; Serum-based sensing; Therapeutic response monitoring; α-Synuclein aggregation

DOI:  https://doi.org/10.1007/s00604-026-08042-2
Protein Sci. 2026 May;35(5): e70565

An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.

Emily J Byrd, Joel A Crossley, Chalmers C C Chau, Paolo Actis, Antonio N Calabrese.

  TAR DNA-binding protein 43 (TDP-43) plays a critical role in RNA metabolism and is incorporated into biomolecular condensates called stress granules. In amyotrophic lateral sclerosis (ALS) and several other neurodegenerative disorders, TDP-43 undergoes aberrant phase transitions, forming insoluble amyloid aggregates, including fibrils composed of solely its intrinsically disordered C-terminal domain (CTD). Despite its central role in disease, the conformational dynamics of the CTD remain poorly understood due to its heterogeneous and transient conformational landscape. Here, we employ native ion mobility-mass spectrometry (IM-MS) using nanopipette sub-micron nano electrospray ionization (nanoESI) emitters to characterize the conformational landscape of wild-type and ALS-associated TDP-43 CTD variants (Q331K and R361S) under different solution conditions. Our data suggest that mutations and salt concentration modulate the CTD's conformations. Combined with thioflavin T fluorescence, light scattering, and microscopy, we reveal that these conformational shifts correlate with altered amyloid assembly kinetics and propensity to form condensates. Notably, the Q331K variant, which has a mutation in the transient α-helical region in the CTD, has reduced propensity to form biomolecular condensates but can undergo amyloid assembly in the absence of condensate formation, suggesting that sequence alterations in this α-helical region can tune the molecular mechanism of amyloid assembly. This study demonstrates the power of IM-MS in probing disordered proteins and reveals mechanistic insights into how disease-associated mutations differentially tune TDP-43 CTD amyloid assembly mechanisms.

Keywords:  Ion mobility–mass spectrometry; TDP‐43 C‐terminal domain; amyloid assembly; biomolecular condensates; intrinsically disordered proteins

DOI:  https://doi.org/10.1002/pro.70565
Biochem Biophys Res Commun. 2026 Apr 09. pii: S0006-291X(26)00487-0. [Epub ahead of print]818 153723

Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential.

Ratna Priya, Goutam Kumar Tanti, Buddhi Prakash Jain.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron loss, leading to muscle weakness, paralysis, and respiratory failure. Dysregulation of RNA metabolism and splicing has emerged as a central mechanism in ALS pathogenesis. TARDBP (TAR DNA-binding protein), FET family proteins (FUS, EWSR1, TAF15), SOD1 (Superoxide Dismutase 1), and C9orf72 (Chromosome 9 Open Reading Frame 72) are key genes associated with ALS that regulate RNA processing, alternative splicing, and nuclear-cytoplasmic transport. Mutations or mislocalization of these proteins result in nuclear loss-of-function and cytoplasmic gain-of-function toxicity, promoting protein aggregation, sequestering spliceosomal components, and impairing spliceosome assembly. This leads to the aberrant inclusion of cryptic exons in essential neuronal genes, such as STMN2 (Stathmin 2) and UNC13A (Unc-13 Homolog A), resulting in the production of truncated proteins, defective axonal maintenance, and impaired synaptic function. TDP-43 pathology, a hallmark of ALS, disrupts splicing and RNA transport, while C9orf72 repeat expansions and FET protein mutations exacerbate cytoplasmic aggregation and stress granule dynamics. Mutant SOD1 contributes via mitochondrial dysfunction, endoplasmic reticulum stress, and disrupted axonal transport. Therapeutic strategies targeting these mechanisms are advancing rapidly. Gene replacement therapy, which restores STMN2 expression, and antisense oligonucleotides (ASOs) targeting mutant transcripts show promise in preclinical and early clinical studies. Complementary approaches, including the inhibition of stress kinases and the activation of autophagy, reduce cytoplasmic protein aggregation and support neuronal homeostasis. This review provides a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS. Understanding the interplay among splicing defects, RNA-binding protein pathology, and neuronal degeneration is critical for developing next-generation multimodal therapies to restore RNA processing, reduce toxic protein accumulation, and promote motor neuron survival.

Keywords:  Alternative splicing; Amyotrophic lateral sclerosis; Exon; RNA binding proteins; RNA processing

DOI:  https://doi.org/10.1016/j.bbrc.2026.153723
Toxicol Appl Pharmacol. 2026 Apr 15. pii: S0041-008X(26)00121-3. [Epub ahead of print] 117825

Impaired autophagy from TRPV4 activation drives α-synuclein pathology in a Parkinson's disease model: A toxicological insight.

Jianhua Hu, Hui Zang, Huixian Li, Wenjing Yang, Jia Luo, Ying Tan, Li Zhuan, Na Liu.

  The environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical agent for modeling Parkinson's disease (PD). Our previous study demonstrated that calcium channel transient receptor potential vanilloid 4 (TRPV4) mediates MPTP-induced endoplasmic reticulum (ER) stress and inflammation, leading to loss of dopamine neurons and movement disorder. Here, we investigated whether TRPV4 activation impairs clearance of pathological α-Synuclein (α-Syn) via the autophagy-lysosomal pathway (ALP), contributing to cognitive deficits in PD. We used C57BL/6J mice subjected to intracerebral injection of adeno-associated virus in substantia nigra to knockdown or overexpress TRPV4, followed by MPTP treatment. Novel object recognition and Morris water maze tests, immunohistochemistry, electron microscopy, and western blot were employed to assess the role of TRPV4 in modulating α-Syn via ALP. We found that targeting TRPV4 to counteract neurotoxicity improved cognitive dysfunction in PD mice. Mechanistically, MPTP-triggered toxic stress and TRPV4 overexpression induced accumulation of α-Syn and autophagosomes in hippocampus. Critically, TRPV4 knockdown significantly alleviated MPTP-induced α-Syn accumulation. Western blot analysis revealed that TRPV4 impaired α-Syn clearance via the ALP, as evidenced by dysregulation of key ALP components: LC3B, p62, lysosome-associated membrane protein 1, and transcription factor EB. In conclusion, our data are consistent with a model in which TRPV4 contributes to α-Syn accumulation through impairment of the ALP. This work establishes a direct link between TRPV4 and impaired α-Syn clearance, identifying TRPV4 not only as a mediator of ER stress and inflammation but as a critical molecular sensor that disrupts proteostasis. This positions TRPV4 as a promising therapeutic target for counteracting MPTP-induced neurodegeneration.

Keywords:  Autophagy-lysosomal pathway; Cognitive disfunction; MPTP; Parkinson's disease; TRPV4; α-Synuclein

DOI:  https://doi.org/10.1016/j.taap.2026.117825
J Chem Inf Model. 2026 Apr 14.

Transient Aggregation-Prone States in Disordered Proteins as Therapeutic Targets: The Amyloid-β Case.

Margherita Bini, Valentina Tozzini, Luca Bellucci.

The amyloid-β (Aβ) peptide is an intrinsically disordered protein whose self-association into toxic oligomers underlies Alzheimer's disease. Because of its dynamic and heterogeneous nature, identifying the conformational states that nucleate aggregation remains a central challenge. In this work, we introduce a chemically interpretable descriptor of amyloidogenic propensity derived from self-docking analyses of conformational ensembles generated through temperature-replica exchange molecular dynamics (T-REMD) using different and complementary force fields. This descriptor classifies individual conformers within the generated ensembles according to their intrinsic aggregation tendency, enabling the identification of metastable, aggregation-prone states. The resulting ensembles reproduce experimental observables, and their classification based on amyloidogenic propensity provides a consistent structural basis for the rationalization and study of these metastable conformers. As a test, we demonstrate that the molecular chaperone DNAJB6, experimentally known to bind amyloidogenic conformations, preferentially interacts with aggregation-prone conformers, thus supporting both the proposed protocol and the consistency of the classification scheme. More broadly, this framework outlines a potentially generalizable strategy to identify metastable states in intrinsically disordered proteins as prospective pharmacological targets to help develop drugs or biomolecules capable of inhibiting the early stages of their aggregation.

DOI: https://doi.org/10.1021/acs.jcim.6c00270
bioRxiv. 2026 Apr 07. pii: 2026.04.04.716514. [Epub ahead of print]

Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood 1-6 . Mitochondrial dysfunction is a common feature of tauopathies 7,8 . Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to tau's physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD + /NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2026.04.04.716514