bims-proned 2026-02-01 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–02–01
fourteen papers selected by
Verena Kohler, Umeå University

Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils.
Concentration-dependent cytoplasmic phase separation of TDP-43 drives aggregation and proteinopathy.
Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
The aggregate proteome of Caenorhabditis elegans mitochondria implicates shared mechanisms of aging and Alzheimer's disease.
Cross-talk between neuroinflammation and α-synuclein aggregation: The central role of the cGAS-STING pathway in Parkinson's disease.
G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.
Phosphorylation of α‑Synuclein Fibrils at S129 Changes DNAJB1 Binding as Probed by Solid-State NMR.
Redox environment modulates aggregation of ataxin-3 in vitro - Implications for drug screening of cysteine-rich proteins.
Site-Specific Aspartic Acid d-Isomerization in Tau R2 and R3 Peptide Seeds Attenuates Seed-Induced Fibril Formation of Full-Length Tau.
TRIM9 and TRIM26 Interact with UBQLN2P497H to Modulate Its Proteasomal Degradation.
Identification of KHS-101 as a Transcription Factor EB Activator to Promote α-Synuclein Degradation.
Antimicrobial peptides inhibit Tau aggregation and modulates its pathology.
Nanomaterial strategies for mitigating protein misfolding and neuroinflammation in neurodegenerative diseases.
Form follows function: morphology as a map of mechanisms in neurodegenerative disease pathology.

ACS Chem Neurosci. 2026 Jan 29.

Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils.

Yana Purvinsh, Mikhail Matveyenka, Dmitry Kurouski.

  Progressive aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of numerous neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and limbic predominant age-related TDP-43 encephalopathy (LATE). This highly conserved nuclear RNA/DNA-binding protein is involved in the regulation of RNA processing. The C-terminal domain (CTD) of TDP-43 plays a key role in protein solubility, cellular localization, and protein-protein interactions. CTD is rich in glycine, glutamine, and asparagine, which facilitate TDP-43 aggregation into amyloid oligomers and fibrils observed in the brain. In this study, we examine the role of lipid bilayers in the aggregation properties of the CTD of TDP-43. We found that lipid bilayers composed of anionic phosphatidylserine and cardiolipin accelerated TDP-43 aggregation. Although lipids did not alter the secondary structure, they altered the cytotoxicity that TDP-43 fibrils exerted to rat dopaminergic cells. Using molecular methods, we showed that TDP-43 fibrils damage cell endosomes. This causes aggregate leakage into the cytosol, where TDP-43 fibrils impair cell autophagy, simultaneously triggering a severe unfolded protein response in the endoplasmic reticulum. Our results indicate that TDP-43 aggregation may be linked to pathological changes in the lipid profiles of neurons.

Keywords:  CTD TDP-43; cardiolipin; neurons; phosphatidylcholine; phosphatidylserine; qPCR

DOI:  https://doi.org/10.1021/acschemneuro.5c00934
FEBS J. 2026 Jan 30.

Concentration-dependent cytoplasmic phase separation of TDP-43 drives aggregation and proteinopathy.

Pauline Combe, Chloé Subecz, Gaïzka Le Goff, Marie Aude Plamont, Delphine Bohl, Zoher Gueroui.

  TDP-43 mislocalization and aggregation are common features of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the mechanisms underlying the transition of nuclear TDP-43 to cytoplasmic aggregates, and their contribution to disease pathogenesis, remain poorly understood. To address this gap, we present a methodology to chemically control the assembly and disassembly of cytoplasmic TDP-43 condensates. By fusing TDP-43 to a phase separation-prone protein scaffold, we can induce the formation of cytoplasmic TDP-43 condensates or, conversely, promote nuclear localization upon addition of a disassembly molecule. TDP-43 accumulates into various assemblies, ranging from submicrometric puncta to larger aggregate-like structures that display hallmarks of proteinopathy in a concentration-dependent manner. Furthermore, oxidative stress drives the maturation of TDP-43 assemblies from puncta into aggregates through interactions with stress granule components. Finally, we show that cytoplasmic TDP-43 aggregates deplete nuclear endogenous TDP-43 and induce cytotoxicity. Collectively, these findings highlight the local cytoplasmic concentration of TDP-43 and stress exposure as key determinants in the onset of TDP-43 proteinopathy, providing a relevant model to study pathological TDP-43 aggregation.

Keywords:  ALS; LLPS; TDP‐43; condensates; phase separation

DOI:  https://doi.org/10.1111/febs.70429
Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.

Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.

  Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.

Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome

DOI:  https://doi.org/10.7554/eLife.95576
Front Aging Neurosci. 2025 ;17 1713391

The aggregate proteome of Caenorhabditis elegans mitochondria implicates shared mechanisms of aging and Alzheimer's disease.

Sonu Pahal, Akshatha Ganne, Meenakshisundaram Balasubramaniam, Sue T Griffin, Robert J Shmookler Reis, Srinivas Ayyadevara.

   Background: Mitochondrial dysfunction and protein aggregation are central features of brain aging and Alzheimer's disease (AD). To define how AD seed proteins modulate these processes, we applied quantitative proteomics to sarkosyl-insoluble aggregates from C. elegans models of normal aging and from worms expressing human Aβ or Tau transgenes.
Results: Normal aging produced a late-onset accrual of mitochondrial proteins within aggregates, implicating impaired energy metabolism and proteostasis collapse. Aβ expression caused a striking expansion and included glycolytic enzymes, tricarboxylic acid cycle components, ribosomal proteins, and trafficking factors, consistent with broad proteostatic and bioenergetic stress, largely overlapping with aging-associated species, yet advanced in onset. Tau expression yielded a smaller set enriched for cytoskeletal, vesicular, and nuclear pore components. Post-translational modifications (4-HNE adducts, phosphorylation, acetylation, methionine oxidation) revealed distinct trajectories: Aβ imposed early oxidative and phosphorylation burden, whereas Tau and aging showed midlife PTM peaks consistent with delayed proteostasis collapse. Cross-species comparison revealed 68 insoluble proteins shared between worm models and human AD brain aggregates. From these, 17 conserved metabolic, chaperone, and trafficking proteins were prioritized by network metrics and validated functionally: RNAi knockdowns aggravated paralysis or impaired chemotaxis, confirming their functional importance.
Conclusion: These findings place mitochondrial proteome collapse at the center of aging and AD-seeded pathology, distinguish Aβ- and Tau-driven proteotoxic routes, and nominate a conserved panel of aggregation-prone proteins as mechanistic drivers and candidate biomarkers for early detection and intervention in AD.

Keywords:  Alzheimer disease; Caenorhabditis elegans; aging; biomarkers; mitochondria; neurodegeneration; protein aggregation; proteomics

DOI:  https://doi.org/10.3389/fnagi.2025.1713391
Cell Signal. 2026 Jan 23. pii: S0898-6568(26)00040-9. [Epub ahead of print]141 112390

Cross-talk between neuroinflammation and α-synuclein aggregation: The central role of the cGAS-STING pathway in Parkinson's disease.

Rong Fu, Lei Shi.

  Parkinson's Disease (PD) is a common neurodegenerative disorder with a complex and incompletely elucidated pathogenesis. Dysregulated immunity plays a pivotal role in the initiation and progression of the disease. The cyclic guanosine monophosphate (GMP)- adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, an intracellular innate immune signaling cascade that has attracted considerable attention in recent years, exerts crucial functions in sensing pathogen invasion and endogenous damage-associated molecular patterns (DAMPs), as well as regulating immune responses. This review thoroughly explores the role of the cGAS-STING pathway in PD immune regulation. It first details the pathway's structural components and activation mechanism, then analyzes its aberrant activation under PD pathological conditions. Furthermore, it discusses in detail the specific mechanisms underlying its role in PD immune regulation, including its impacts on microglial activation, inflammatory cytokine release, α-synuclein (α-syn) aggregation and clearance, as well as neuronal survival. Meanwhile, it summarizes the current research progress in targeting the cGAS-STING pathway for PD treatment. Finally, it points out the existing challenges and future research directions in this field, aiming to provide novel insights and theoretical foundations for investigating PD pathogenesis and developing clinical therapeutic strategies.

Keywords:  Immune regulation; Inflammatory response; Microglia; Parkinson's disease; cGAS-STING pathway; α-Syn

DOI:  https://doi.org/10.1016/j.cellsig.2026.112390
Antioxidants (Basel). 2025 Dec 19. pii: 5. [Epub ahead of print]15(1):

G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.

Alan Herbert.

  Expansion of d(GGGGC)n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer's Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.

Keywords:  ALS; Amyloid-beta; C9ORF72; FTD; G-quadruplex; TDP43; dementia; flipons; heme; oxidative stress

DOI:  https://doi.org/10.3390/antiox15010005
JACS Au. 2026 Jan 26. 6(1): 343-356

Phosphorylation of α‑Synuclein Fibrils at S129 Changes DNAJB1 Binding as Probed by Solid-State NMR.

Sayuri Pacheco, Dhanya S Reselammal, Shanlong Li, Qingya Zhang, Gauri Velloor, Jianhan Chen, Ansgar B Siemer.

  Amyloid fibrils formed by the protein α-synuclein are implicated in the pathogenesis of synucleinopathies. In addition to their rigid cross-β core, these fibrils have intrinsically disordered regions on their surface, which are important for interactions with other cellular components, such as chaperones. Chaperones play a vital role in preventing and reversing amyloid formation in neurodegenerative diseases. How they recognize misfolded proteins is an active field of research. DNAJB1 is a cochaperone that recognizes fibrils and recruits other chaperones such as Hsp70 and Apg2, which collectively disaggregate fibrils formed by α-synuclein, tau, and huntingtin. Because DNAJB1 was reported to bind the C-terminus of α-synuclein and S129 in this C-terminus is predominantly phosphorylated in patient-derived fibrils, we wanted to determine the effect of this post-translational modification on DNAJB1 binding. Using electron micrographs, NMR spectroscopy, and binding assays, we show that phosphorylation at S129 reduces the dynamics of the intrinsically disordered C-terminus of α-synuclein fibrils and increases the binding of DNAJB1 to this very C-terminus. MD simulations further suggest that the reduced dynamics is due to increased interaction of the phosphorylated C-terminus with the fibril core. DNAJB1 binds the exact same region at the C-terminus, indicating the phosphorylation at S129 might have a dual effect of reducing fibril surface dynamics and increasing chaperone recognition.

Keywords:  DNAJB1; J-proteins; amyloid fibrils; chaperone; phosphorylation; post-translational modifications; solid-state NMR; α-synuclein

DOI:  https://doi.org/10.1021/jacsau.5c01266
FEBS J. 2026 Jan 29.

Redox environment modulates aggregation of ataxin-3 in vitro - Implications for drug screening of cysteine-rich proteins.

Martyna Podlasiak, Martina Sollazzo, Elisa Monaca, Raffaele Sabbatella, Maria Agnese Morando, Oleg Chertkov, Laura Puglisi, Martina Mascellino, Anna Fricano, Sandra Macedo-Ribeiro, Caterina Alfano.

  Spinocerebellar ataxia type 3 is a debilitating neurodegenerative disorder driven by the pathological aggregation of ataxin-3 (Atx3), a deubiquitinating enzyme with a cysteine-rich catalytic domain and an expandable polyglutamine (polyQ) tract. While the role of polyQ expansion in Atx3 aggregation is well documented, the influence of redox conditions on its self-assembly remains underexplored. Here, we demonstrate that reducing agents and a redox environment critically modulate Atx3 aggregation by regulating disulfide bond formation within the Josephin domain. We demonstrate that dithiothreitol (DTT), through progressive oxidation, promotes the formation of non-native and disulfide-linked conformers, which may serve as nucleation centers for fibril formation. In contrast, tris(2-carboxyethyl)phosphine preserves cysteine residues of Atx3 in the reduced state and inhibits aggregation, but concomitantly promotes cleavage of full-length Atx3. Furthermore, we identify a previously underappreciated role for 4,5-dihydroxy-1,2-dithiane, the DTT oxidation product, in directly triggering Atx3 aggregation. We also demonstrate that running aggregation assays at 50 °C circumvents the redox dependency of Atx3 aggregation, thereby streamlining the aggregation process and enabling the use of a simplified, robust platform for medium- to high-throughput screening of aggregation modulators. These findings provide new insights into the redox-dependent modulation of Atx3 aggregation and highlight critical considerations for in vitro aggregation assays of cysteine-rich proteins, with broad implications for therapeutic strategies targeting cysteine-rich, aggregation-prone proteins in neurodegenerative diseases. Although our study focuses on in vitro investigation, it suggests that redox dysregulation in cells could promote pathogenic aggregation of Atx3, reinforcing the link between cellular redox balance and polyglutamine disease progression.

Keywords:  SCA3; ataxin‐3; neurodegeneration; polyglutamine diseases; protein aggregation; redox‐dependent aggregation

DOI:  https://doi.org/10.1111/febs.70426
Biomolecules. 2026 Jan 13. pii: 143. [Epub ahead of print]16(1):

Site-Specific Aspartic Acid d-Isomerization in Tau R2 and R3 Peptide Seeds Attenuates Seed-Induced Fibril Formation of Full-Length Tau.

Genta Ito, Takuya Murata, Noriko Isoo, Toshihiro Hayashi, Naoko Utsunomiya-Tate.

  The aggregation of tau protein is a central pathological event in Alzheimer's disease, and this pathology is hypothesized to spread via a prion-like mechanism driven by tau "seeds". While aggregated tau from Alzheimer's disease brains is known to contain age-related d-isomerized aspartic acid (d-Asp) residues, it remains unknown how this modification affects the seeding activity that drives disease propagation. Here, we investigated the impact of site-specific d-isomerization within R2 and R3 tau repeat-domain peptides, which form the core of tau fibrils. We demonstrate that the stereochemical integrity of these peptides is critical for their seeding function. d-isomerization at Asp314 within the R3 peptide seed severely impaired its ability to template the fibrillization of full-length tau in vitro. This finding was validated in a cellular model, where R3 seeds containing d-Asp314 were significantly less potent at inducing the formation of phosphorylated tau aggregates compared to wild-type seeds. Our results establish that Asp d-isomerization within tau seeds acts as a potent attenuator of their pathological seeding activity, suggesting this spontaneous modification may intrinsically modulate the progression of Alzheimer's disease.

Keywords:  D-aspartate; isomerization; tau

DOI:  https://doi.org/10.3390/biom16010143
ACS Chem Biol. 2026 Jan 25.

TRIM9 and TRIM26 Interact with UBQLN2P497H to Modulate Its Proteasomal Degradation.

Xingyuan Chen, Zhongwen Cao, Xiaochen Liang, Ting Zhao, Yinsheng Wang.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. ALS-linked mutations in UBQLN2 promote protein aggregation and disrupt proteostasis, yet the mutation-specific protein interactomes and their functional relevance remain poorly defined. We employed APEX2 proximity labeling, together with affinity enrichment of biotinylated peptides and LC-MS/MS analysis, to profile the interactomes of wild-type UBQLN2 and two ALS-linked variants, UBQLN2P497H and UBQLN2P497S. We identified 785 unique biotinylated proteins, many of which exhibit augmented enrichment in the proximity proteomes of the two mutants over wild-type UBQLN2. Notably, the E3 ubiquitin ligases TRIM9 and TRIM26 were selectively enriched in the proximity proteome of UBQLN2P497H, which we validated by coimmunoprecipitation followed by Western blot analysis. Fractionation analysis revealed coaccumulation of TRIM9 and TRIM26 with UBQLN2P497H in the insoluble fraction, consistent with its heightened aggregation propensity. Treatment of UBQLN2P497H-expressing cells with a proteasomal inhibitor led to elevated accumulation of a C-terminal UBQLN2 fragment that is absent in cells expressing wild-type UBQLN2 or its P497S mutant. Individual knockdown of TRIM9 and TRIM26 significantly increased the abundance of the fragment, establishing UBQLN2P497H as a substrate for TRIM9- and TRIM26-mediated ubiquitinylation and subsequent proteasomal degradation. These findings nominate TRIM9 and TRIM26 as specific interactors of UBQLN2P497H and as regulators of a previously underexplored C-terminal UBQLN2 fragment, suggesting that impaired clearance of this species may contribute to ALS pathogenesis.

DOI: https://doi.org/10.1021/acschembio.5c00911
Int J Mol Sci. 2026 Jan 16. pii: 905. [Epub ahead of print]27(2):

Identification of KHS-101 as a Transcription Factor EB Activator to Promote α-Synuclein Degradation.

Haizhen Zhu, Anqi Ren, Ting Li, Tao Zhou, Ailing Li, Xin Pan, Liang Chen, Jiayi Chen.

  Neurodegenerative disorders are increasingly linked to a progressive decline in lysosomal function. Activating Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has therefore emerged as a promising therapeutic strategy to enhance cellular clearance in these conditions. In this study, we identified KHS-101 as a novel TFEB activator through a high-throughput screen of blood-brain-barrier-permeable small molecules. We demonstrated that KHS-101 promotes TFEB nuclear translocation, enhances lysosomal biogenesis and proteolytic activity, and increases autophagic flux. Furthermore, KHS-101 significantly accelerates the degradation of pathogenic A53T mutant α-synuclein in a cellular model of Parkinson's disease, suggesting its potential to mitigate α-synuclein-mediated proteotoxicity and hold neuroprotective potential. Our findings identify KHS-101 as a potent TFEB activator and highlight the therapeutic potential of modulating the autophagy-lysosomal pathway for treating Parkinson's disease and related disorders.

Keywords:  KHS-101; Parkinson’s disease; TFEB; autophagy–lysosome pathway; lysosome degradation; α-synuclein

DOI:  https://doi.org/10.3390/ijms27020905
Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00086-0. [Epub ahead of print]149 375-394

Antimicrobial peptides inhibit Tau aggregation and modulates its pathology.

Subashchandrabose Chinnathambi, Nagaraj Rangappa, Sneha Malik.

  Alzheimer's disease is mainly caused by two proteins, Tau and Amyloid-β. While there are several cures currently being explored for it, there is no cure yet for the disease progression and prevention, but only those to alleviate the symptoms. One of the hypothesis for the cause of the Alzheimer's disease is the microbial hypothesis. This suggests that there are a lot of microorganisms present in our body which can contribute to the disease pathology by leading to symptoms such as neuroinflammation. Our body has certain molecules to maintain innate immunity, known as antimicrobial peptides. Recently, several studies suggest the roles of these molecules in the Alzheimer's disease as therapeutic molecules and as biomarkers. Amyloid beta which is one of the major proteins is suggested to be an antimicrobial peptide on its own. The formation of its oligomers and plaques is due to neuroprotective reasons. A similar theory exists for the formation of neurofibrillary tangles (NFTs) from Tau. There include lactoferrin, LL-37 and defensins. They are often found in association with the aggregated proteins, amyloid beta and Tau. Additionally, fluctuations in their levels are often observed in several fluids and regions inside in patients with AD compared to the control cohorts. While their therapeutic potential has been proven, their mechanisms of action, effectivity and expedition towards clinical studies is yet to be done.

Keywords:  Alzheimer’s disease; Amyloid-β; Antimicrobial peptides; Tau

DOI:  https://doi.org/10.1016/bs.apcsb.2025.09.002
Zool Res. 2026 Jan 18. pii: 2095-8137(2026)01-0155-33. [Epub ahead of print]47(1): 155-187

Nanomaterial strategies for mitigating protein misfolding and neuroinflammation in neurodegenerative diseases.

Yu-He Wang, Xiao-Ling Lang, Xiu-Li Qing.

  Neurodegenerative disorders such as Alzheimer's disease are characterized by pathological protein misfolding, persistent neuroinflammation, and progressive synaptic deterioration. Nanoscale therapeutic platforms offer a versatile strategy for simultaneously suppressing pathogenic protein aggregation and modulating glial hyperactivation, thereby addressing the multifactorial nature of neurodegenerative pathology. Engineered AuNPs, carbon-based nanodots, and related constructs with negatively charged surfaces exhibit high affinity for amyloidogenic peptides, thereby limiting amyloid-β or tau fibrillization, while photothermal strategies using graphene or gold nanorods induce localized thermal disruption of preformed aggregates, enhancing their disassembly. In parallel, functionalized nanocarriers facilitate brain-targeted delivery of anti-inflammatory agents by leveraging receptor-mediated transcytosis or biomimetic cell membrane-camouflaging strategies, attenuating proinflammatory cytokines and promoting autophagic clearance. In vitro and in vivo models demonstrate integrated therapeutic benefits, including attenuation of plaque deposition, preservation of neuronal integrity, and recovery of cognitive performance. Despite remaining challenges in large-scale synthesis and long-term safety, evolving nanotechnologies offer a flexible and integrated platform capable of disrupting the pathogenic cycle linking protein misfolding, neuroinflammation, and disease progression.

Keywords:  Alzheimer’s disease; Nanomaterial; Neuroinflammation; Protein misfolding

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2025.227
Free Neuropathol. 2026 ;7 4

Form follows function: morphology as a map of mechanisms in neurodegenerative disease pathology.

Edward B Lee.

  Across neurodegenerative diseases, the shape and spatial organization of pathology carry rich mechanistic information. Vacuoles, spongiosis, oligodendroglial coiled bodies, dendritic dystrophic neurites, amyloid plaque compactness, and phase-separated droplets each reflect distinct cellular identities, subcellular compartments, trafficking pathways, and biophysical material states. Here, I synthesize morphological signatures across neurodegenerative diseases to propose a framework that links morphology to mechanism. Morphology is neither incidental nor merely descriptive. Rather, it is a readout of the basic mechanisms that govern self-assembly of proteins into aggregates, the cell's attempts at proteostasis (clearance, sequestration, and transport), and the failure that ensues.

Keywords:  Aggregate; Amyloid; Inclusion; Proteostasis; Tau; Transport

DOI:  https://doi.org/10.17879/freeneuropathology-2026-9241