bims-proned 2026-10-11 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–10–11
nine papers selected by
Verena Kohler, Umeå University

Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.
A Live-Cell Imaging System for the Identification of Pro- and Anti-Aggregatory α-Synuclein Modulators.
SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.
Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities.
One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.
Increased Expression of α-Synuclein Impairs Trafficking of the Essential SNARE Protein Synaptobrevin-2.
A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues.
Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.
Biased stochastic motor dynamics drive bidirectional, processive translocation by the AAA+ disaggregase Hsp104.

Expert Opin Ther Targets. 2026 Oct 09.

Targeting protein misfolding and aggregation in neurodegenerative diseases: challenges for the identification and validation of targets for small molecules.

Arunabh Choudhury, Sneh Prabha, Mohammad Umar Saeed, Md Nayab Sulaimani, Md Imtaiyaz Hassan.

   INTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and related proteinopathies are characterized by the misfolding, aggregation, and accumulation of specific proteins that disrupt neuronal homeostasis, leading to neuronal death. Despite major advances in structural biology and molecular neuroscience, identifying and validating druggable targets in neurodegenerative diseases remains challenging. Many involved proteins are intrinsically disordered, exhibit conformational heterogeneity, and form highly dynamic toxic species.
AREAS COVERED: This review summarizes the mechanisms of protein folding, misfolding, aggregation, and prion-like propagation in major neurodegenerative proteinopathies, including amyloid-beta and tau in Alzheimer's disease, alpha-synuclein in synucleinopathies, TDP-43 and FUS in ALS/FTLD, polyglutamine-expanded proteins, prion proteins, and rare hereditary amyloidosis. We also discuss major barriers to target identification and validation, including conformational flexibility, oligomer toxicity, blood-brain barrier penetration, and target engagement complexity. Finally, we highlight emerging strategies integrating structural biology, computational methods, and improved experimental models to discover small-molecule inhibitors for neurodegenerative diseases.
EXPERT OPINION: Effective therapeutic discovery will require moving beyond single-target models toward ensemble-based validation strategies. Integrating structural biology, advanced imaging, biomarkers, and computational approaches may improve the identification of druggable targets and support precision-medicine-based interventions for neurodegenerative diseases.

Keywords:  Intrinsically disordered proteins; Small-molecule inhibitors; neurodegenerative diseases; protein aggregation; protein misfolding

DOI:  https://doi.org/10.1080/14728222.2026.2747518
Mol Neurobiol. 2026 Oct 06. pii: 949. [Epub ahead of print]63(1):

A Live-Cell Imaging System for the Identification of Pro- and Anti-Aggregatory α-Synuclein Modulators.

Tzukit Tal, Yael Almog, Ortal Iancu Cohen, Lihi Radomir, Dana Bar-On, Ianai Fishbein, Eran Meshorer.

  α-Synuclein (αSyn) aggregation is a defining pathological feature of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy (MSA). However, existing in vitro methods to monitor αSyn aggregation often rely on endpoint assays that cannot distinguish monomeric from oligomeric species or capture early aggregation dynamics. Here, we implement an αSyn bimolecular fluorescence complementation (αSyn-BiFC) strategy in a stable human glial-derived cell system optimized for real-time, high-content analysis of early αSyn self-association events and their modulation. In this strategy, αSyn is fused to complementary fragments of the Venus fluorescent protein, enabling real-time visualization of αSyn-αSyn interactions during oligomer formation. Using U373 human astrocytoma cells, a scalable glial-derived cell line previously used in studies of MSA, we established both transient and stable αSyn-BiFC expression systems. We demonstrate that reconstituted Venus fluorescence correlates with pSer129 αSyn immunostaining, supporting the association of the BiFC signal with pathology-related αSyn assemblies. The model responded robustly to multiple stressors known to promote αSyn aggregation, including proteostasis disruption (leupeptin, MG132), ER stress (tunicamycin), and environmental toxins (rotenone), while iron, particularly Fe3⁺, also enhanced αSyn self-association. Furthermore, testing two small molecules previously shown to attenuate αSyn aggregation and pathology in vivo revealed a reduction in Venus fluorescence, consistent with reduced αSyn self-association and supporting the platform's utility for drug discovery screens. By providing a dynamic, sensitive, and physiologically relevant readout of early αSyn assemblies, the αSyn-BiFC model overcomes limitations of conventional assays and offers a scalable framework for mechanistic studies, compound screening, and integration into more disease-relevant neuronal and aging-enhanced models for future synucleinopathies research.

Keywords:  Aggregation; Alpha-synuclein; BiFC; Bimolecular fluorescence complementation; Drug screening; High-content imaging; Live-cell imaging; Synucleinopathies; U373 cells

DOI:  https://doi.org/10.1007/s12035-026-06248-2
Acta Neuropathol. 2026 Oct 06. pii: 43. [Epub ahead of print]152(1):

SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.

Evellyn Mayla de Azevedo, Victoria Simões Bernardo, Marcelo M S Lima, Elis Cristina Araujo Eleutherio, Tiago Fleming Outeiro.

  Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.

Keywords:  ALS; Co-pathologies; FTD; Neuropathology; Protein aggregation

DOI:  https://doi.org/10.1007/s00401-026-03090-7
J Huntingtons Dis. 2026 Oct 09. 18796397261494078

Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities.

Florence Dm Wavreil, Sabine Schipper-Krom, Eric Aj Reits.

  Huntington's Disease (HD) is a progressive neurodegenerative disease that is caused by a CAG-repeat expansion in the exon 1 of the huntingtin (HTT) gene, which results in the formation of toxic mutant HTT (mHTT) exon 1 fragments with expanded polyglutamine (polyQ) stretch. These mHTT fragments are prone to misfolding and aggregation, causing cytotoxicity, particularly in the striatal neurons. The lack of disease-modifying treatments for HD emphasizes the need to develop new therapeutic strategies to prevent or reverse HD pathology. The reduction of the mHTT exon 1 fragment by facilitating its selective degradation may be a promising approach to prevent aggregation, thereby delaying or preventing the onset of HD. Since the ubiquitin-proteasome system (UPS) is not impaired in HD, enabling strategies to selectively target mHTT towards the UPS or autophagy would improve mHTT clearance. In this review, we describe three main strategies to modulate mHTT levels. First, we discuss different ubiquitin-modifying enzymes that have been associated with HTT and may act as possible therapeutic targets. Next, we focus on more targeted approaches for the selective degradation of mHTT with engineered small molecule compounds such as PROTACs and AUTOTACs. Finally, we summarize the current knowledge of HTT-specific intracellular antibodies (intrabodies) as potential candidates for gene therapy. Together, this review aims to assess different possible avenues for the treatment of HD.

Keywords:  autophagy; huntingtin; intrabodies; proteasome; proteostasis; small molecule compounds

DOI:  https://doi.org/10.1177/18796397261494078
Front Neurosci. 2026 ;20 1941231

One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.

Robert C C Mercer.

  Protein misfolding neurodegenerative diseases are invariably fatal conditions with a paucity of available and universally embraced disease modifying therapies. It is crucial, therefore, to identify additional potential candidate molecules and/or targets with which to work toward human trials. In this mini-review, I will highlight the recent discoveries of compounds that physically associate with the lysosome to enhance or restore its activity. One potential target for the development of additional therapeutics that emerges from the consideration of these molecules is the proton pump responsible for acidification of the lysosomal lumen, the vacuolar H+-ATPase. While the approach of directly targeting lysosomal activity remains experimental at present, the wealth of evidence pointing to the involvement of the endolysosomal-autophagic system across protein misfolding neurodegenerative diseases raises the tantalizing possibility that this therapeutic modality could have broad applicability.

Keywords:  Aβ; TDP-43; lysosome; neurodegeneration; prion; tau; therapeutics; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2026.1941231
J Neurochem. 2026 Oct;170(10): e70568

Increased Expression of α-Synuclein Impairs Trafficking of the Essential SNARE Protein Synaptobrevin-2.

Elyas H Arvell, James P Carroll, Joshua Saito, Holly Melland, Ranjith R Unnithan, Chris French, Danny M Hatters, Sarah L Gordon.

  α-Synuclein is a presynaptic protein that has been extensively studied for its role in Parkinson's disease. Multiplication and missense variants in the gene encoding α-synuclein are causes of familial PD, and aggregated α-synuclein is a major component of Lewy bodies and Lewy neurites, the histopathological hallmark of the disease. However, the native function of α-synuclein remains unclear, though several lines of evidence suggest it modulates presynaptic function. α-Synuclein binds the vesicular SNARE protein synaptobrevin-2/VAMP2, and increased levels of α-synuclein potentiate SNARE complex levels without impacting exocytic rate. Given the essential role of synaptobrevin-2 in synaptic function we sought to examine how increased expression of α-synuclein, at levels observed in familial synucleinopathies with SNCA triplication, impacts the trafficking of this essential SNARE protein. Modest (approximately 2-fold) overexpression of α-synuclein in cultured murine hippocampal neurons caused a slowing in the endocytic retrieval of synaptobrevin-2, without impacting either the targeting of the protein to synapses or altering endocytosis. We also show that α-synuclein is not working antagonistically with the synaptobrevin-2 chaperone synaptophysin, and likely acts at least partially via direct binding to synaptobrevin-2. Finally, increased expression of α-synuclein induces synaptic depression upon repeated neuronal depolarisation, in a manner requiring binding to synaptobrevin-2. We reveal α-synuclein as a modulator of synaptobrevin-2 endocytic trafficking and highlight perturbed SNARE protein trafficking as a potential contributor to synaptic dysfunction and neuronal health in Parkinson's disease.

Keywords:  Parkinson's disease; endocytosis; neurotransmission; protein trafficking; synaptobrevin‐2; α‐synuclein

DOI:  https://doi.org/10.1111/jnc.70568
Sci Adv. 2026 Oct 09. 12(41): eady6048

A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues.

Joud Hirbawi, Adam Zaretsky, Huadong Zhu, Uri Goshtchevsky, Gourab Dey, Emmanuelle Merquiol, Atif Ahmed Siddiqui, Irit Cohen, Galia Blum, Ehud Cohen.

The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN's competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that reducing the expression of gtr-1, which encodes a neuronal heterotrimeric guanine nucleotide-binding protein-coupled receptor, mitigates the toxicity of the Alzheimer's disease cause, Aβ peptide. Here, we investigated the mechanism that is acted upon the knockdown of gtr-1 and found that it differentially modulates gene expression profiles, including of neuropeptide-coding genes, and dissimilarly modifies protein aggregation in worms that express distinct proteotoxic proteins. The knockdown of gtr-1 also enhances protein degradation. These findings highlight the roles of neuropeptides as organismal coordinators of proteostasis in the face of distinct proteotoxic challenges.

DOI: https://doi.org/10.1126/sciadv.ady6048
Front Neurosci. 2026 ;20 1913175

Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.

Danielle Brink, Rensu Theart, Benjamin Loos.

  Neurodegenerative diseases are characterized by progressive neuronal loss and the accumulation of misfolded proteins. In Alzheimer's disease, several pathogenic protein species, including amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein, are known substrates of macroautophagy. However, the extent to which macroautophagy selectively engages these proteins for degradation under conditions of proteotoxic stress remains poorly understood. Here, the contribution of specifically macroautophagy to the degradation of amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein was investigated using an amyloid precursor protein overexpression model. Mouse neuroblastoma N2A cells stably expressing the human Swedish amyloid precursor protein mutation were treated with butyric acid for 24 and 48 h to produce increasing proteotoxicity and molecular pathology. Autophagic flux was assessed using bafilomycin A1 and protein abundance quantified by western blotting. Confocal microscopy and colocalization analysis was performed to examine intracellular protein localization and recruitment to the autophagy compartment. Amyloid precursor protein overexpression and autophagosome/lysosome fusion inhibition elicited distinct protein-specific responses, with phosphorylated tau showing highest accumulation and autophagic recruitment. In contrast, tau and amyloid precursor protein exhibited moderate increases, while alpha-synuclein and amyloid beta showed differential and limited responses upon macroautophagy inhibition. Collectively, these findings suggest that the autophagy molecular machinery does not engage uniformly with Alzheimer's disease-associated proteins but may be characterized by a highly differential cargo engagement under amyloid precursor protein-driven proteotoxic stress. Phosphorylated tau emerged as the earliest and most prominent protein to be target to the autophagy compartment, highlighting its potential importance in disease progression and therapeutic intervention.

Keywords:  Alzheimer's disease; amyloid; autophagy; fluorescence; neurodegenerative disease

DOI:  https://doi.org/10.3389/fnins.2026.1913175
bioRxiv. 2026 Aug 10. pii: 2026.08.09.743785. [Epub ahead of print]

Biased stochastic motor dynamics drive bidirectional, processive translocation by the AAA+ disaggregase Hsp104.

JiaBei Lin, Jaskamaljot Kaur Banwait, Ayush Saurabh, Kim A Sharp, Daniel R Southworth, Steve Pressé, Aaron L Lucius, Yale E Goldman, James Shorter.

Protein aggregation disrupts proteostasis and drives neurodegeneration. Hsp104 is a hexameric, ring-shaped AAA+ ATPase that dissolves protein aggregates, yet how hexamers translocate and extract polypeptides trapped in mechanically resistant aggregates remains unclear. Using substrates that recapitulate the physical constraints of aggregates, we establish that Hsp104 is a processive, bidirectional translocase that can dynamically switch direction while threading a single polypeptide. On mechanically restrained substrates and prions, Hsp104 hexamers execute biased stochastic transitions among three conformational states at individual interprotomer interfaces: closed, extended, and a previously unobserved hyperextended form. These transitions follow kinetically favored paths rather than a rigid rotary sequence. The resulting biased stochastic stepping, enabled by the conformational plasticity of Hsp104 hexamers, underpins operational adaptability and redefines the functional logic of AAA+ motors.

DOI: https://doi.org/10.64898/2026.08.09.743785