bims-proned 2025-08-17 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–08–17
twenty papers selected by
Verena Kohler, Umeå University

Perilla-derived chalcone inhibits α-synuclein fibrillization and prevents aggregate-induced disruption of intracellular α-synuclein conformation in neuronal cells.
Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities.
Multivalent interaction induces phase separation and formation of more toxic aggregates of α-syn in a yeast model of Parkinson's disease.
HAPLN2 forms aggregates and promotes microglial inflammation during brain aging in mice.
Formic acid impairs α-synuclein seeding activity in human and mouse brains.
Development and Characterization of a Novel α-Synuclein-PEST H4 Cell Line for Enhanced Drug Screening in α-Synucleinopathies.
Advances in PET imaging of protein aggregates associated with neurodegenerative disease.
Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?
Client-scaffold interactions suppress aggregation of a client protein in model condensates.
Strain-specific effects of Desulfovibrio on neurodegeneration and oxidative stress in a Caenorhabditis elegans PD model.
Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.
Amino acid osmolytes disrupting intradomain interactions reduce the amyloidogenicity of α-synuclein: studies with charged l-amino acids and their derivatives.
Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology.
α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.
High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs.
N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo state.
Mechanism of inhibition of acid-mediated transthyretin aggregation by designed peptides.
Nigrostriatal dopaminergic vulnerability in Parkinson's disease: Neuroprotective strategies.
Neuroprotective mechanism of LincRNA in neurodegenerative diseases.
DJ-1 in Parkinson's disease: Its important role at endoplasmic reticulum-mitochondria contact sites.

Biochem Biophys Res Commun. 2025 Aug 06. pii: S0006-291X(25)01167-2. [Epub ahead of print]779 152452

Perilla-derived chalcone inhibits α-synuclein fibrillization and prevents aggregate-induced disruption of intracellular α-synuclein conformation in neuronal cells.

Yasuhiko Izumi, Naoto Kondo, Akinori Akaike, Yutaka Koyama, Toshiaki Kume.

  The pathological aggregation of α-synuclein (α-syn) is a hallmark of Parkinson's disease, where extracellular α-syn aggregates can disrupt intracellular α-synuclein conformation in neurons. In this study, we investigated the impact of 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC), isolated from green perilla, on α-syn fibrillization and subsequently on intracellular α-synuclein conformation. DDC concentration-dependently inhibited α-syn fibrillization in vitro, as determined by thioflavin S fluorescence and blue native polyacrylamide gel electrophoresis. DDC also disaggregated preformed α-syn fibrils, as indicated by decreased thioflavin S fluorescence. Structure-activity relationship analysis revealed that both the 2',3'-dihydroxy and 4',6'-dimethoxy substituents on the B-ring contributed to the inhibitory effect of DDC on α-syn fibrillization. Exposure of SH-SY5Y cells overexpressing α-synuclein to extracellular aged α-syn (i.e., fibrillized α-syn prepared by shaking) significantly reduced diffuse C-terminal α-syn immunoreactivity. Co-incubation of DDC during the fibrillization process preserved this diffuse staining, whereas adding it after fibrillization to preformed α-syn fibrils further diminished it. However, the direct addition of 30 μM DDC to the culture medium significantly attenuated the loss of diffuse C-terminal α-syn immunoreactivity caused by aged α-syn, likely due to a higher DDC-α-syn ratio. These findings demonstrate that DDC not only inhibited α-syn aggregation but also prevented the aggregate-induced conformational disruption of intracellular α-synuclein, highlighting its potential as a therapeutic agent against synucleinopathies.

Keywords:  Chalcone; Disaggregation; Protofibril; Synucleinopathy; α-synuclein aggregation

DOI:  https://doi.org/10.1016/j.bbrc.2025.152452
Nat Commun. 2025 Aug 09. 16(1): 7368

Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities.

Shuyi Zeng, Xingyu Xiong, Houfang Long, Qianhui Xu, Yifan Yu, Bo Sun, Cong Liu, Zhizhi Wang, Wenqing Xu, Shengnan Zhang, Dan Li.

Parkinson's disease (PD) is characterized by the accumulation and spread of pathological α-synuclein (α-syn) fibrils, which contribute to neuroinflammation and neurodegeneration. Here we show that two immunoglobulin-like (Ig-like) domains derived from α-syn receptors, the D1 domain of lymphocyte-activation gene 3 (L3D1) and the V domain of advanced glycation end-products (vRAGE), effectively block cell surface binding of α-syn fibrils, suppress fibrils-induced neuronal α-syn aggregation, and reduce inflammatory responses in microglia. Building on this, we identified two additional Ig-like binders, the D1 domain of cluster of differentiation 4 (CD4 D1) and the D1 domain of chimeric antigen receptor (CAR D1), that target the C-terminal region of α-syn fibrils and mitigate fibrils-induced pathological activities. A structure-guided mutant, CAR D1_Mut, exhibits enhanced binding affinity and functional efficacy. These findings highlight the potential of Ig-like binders as molecular tools to interfere with pathological α-syn interactions.

DOI: https://doi.org/10.1038/s41467-025-62755-1
Protein Sci. 2025 Sep;34(9): e70253

Multivalent interaction induces phase separation and formation of more toxic aggregates of α-syn in a yeast model of Parkinson's disease.

Rajeev Jain, Sharavanakkumar Sk, Krishnananda Chattopadhyay.

  The process of protein phase separation, particularly in the context of intrinsically disordered proteins, has been extensively studied for its implications in several neurodegenerative diseases. Although the mechanism of protein phase separation and the involved molecular grammar have been well explored under in vitro conditions, the focus is now shifting toward developing more complex models of phase separation in order to mimic the biological systems closely. Here, we studied the phase separation of alpha synuclein (α-syn), an intrinsically disordered protein whose aggregation is implicated in the pathology of Parkinson's disease inside yeast cells (Saccharomyces cerevisiae). Using a positively charged polymer, polyethylenimine (PEI), which binds presumably at the negatively charged C-terminal domain of α-syn, we find that the aggregation of α-syn inside yeast can be modulated by at least two pathways: one involving phase separation and the second one without phase separation. We find further that these two pathways lead to varying fibril characteristics and toxicities. We believe that this model can be used as a quick and convenient system to screen novel and repurposed small molecules against toxic protein droplets.

Keywords:  Parkinson's disease; liquid–liquid phase separation; neuro‐degenerative disorders; protein aggregation; yeast; α‐Synuclein

DOI:  https://doi.org/10.1002/pro.70253
PLoS Biol. 2025 Aug 14. 23(8): e3003006

HAPLN2 forms aggregates and promotes microglial inflammation during brain aging in mice.

Ayaka Watanabe, Shoshiro Hirayama, Itsuki Kominato, Sybille Marchese, Pietro Esposito, Vanya Metodieva, Taeko Kimura, Hiroshi Kameda, Terunori Sano, Masaki Takao, Sho Takatori, Masato Koike, Juan Alberto Varela, Taisuke Tomita, Shigeo Murata.

Protein aggregation is a hallmark of neurodegenerative diseases and is also observed in the brains of elderly individuals without such conditions, suggesting that aging drives the accumulation of protein aggregates. However, the comprehensive understanding of age-dependent protein aggregates involved in brain aging remains unclear. Here, we investigated proteins that become sarkosyl-insoluble with age and identified hyaluronan and proteoglycan link protein 2 (HAPLN2), a hyaluronic acid-binding protein of the extracellular matrix at the nodes of Ranvier, as an age-dependent aggregating protein in mouse brains. Elevated hyaluronic acid levels and impaired microglial function reduced the clearance of HAPLN2, leading to its accumulation. HAPLN2 oligomers induced microglial inflammatory responses both in vitro and in vivo. Furthermore, age-associated HAPLN2 aggregation was also observed in the human cerebellum. These findings suggest that HAPLN2 aggregation results from age-related decline in brain homeostasis and may exacerbate the brain environment by activating microglia. This study provides new insights into the mechanisms underlying cerebellar aging and highlights the role of HAPLN2 in age-associated changes in the brain.

DOI: https://doi.org/10.1371/journal.pbio.3003006
bioRxiv. 2025 Jul 18. pii: 2025.07.14.664807. [Epub ahead of print]

Formic acid impairs α-synuclein seeding activity in human and mouse brains.

Saumya Digraskar, George Dobbins, Piyali Das, Ryan Bash, Abigail Songer, Jaewon Huh, Kasandra Scholz, Musaab Khan, Matthew S Goldberg, Marla Gearing, Laura Volpicelli-Daley, Shu Chen, Patricia Aguilar-Calvo.

α-Synuclein (α-syn) is an abundant monomeric protein that can aggregate into fibrils and form neuropathological inclusions in the brains of patients with synucleinopathies. New evidence suggests that the mouse-human transmission barrier of α-syn is lower than previously reported, emphasizing the need for improved biosafety procedures when working with α-syn aggregates. Histopathology of α-syn-infected brain represents a significant potential source of occupational exposure, and current methods for tissue fixation do not inactivate the ability of pathologic α-syn to seed the conversion of endogenous, monomeric α-syn into fibrils. In this study, we tested whether 96% formic acid treatment could reduce the seeding activity of α-syn aggregates in paraformaldehyde-fixed brain samples from dementia with Lewy bodies (DLB) patients and α-syn pre-formed fibrils (PFF)-injected mouse brains. Using real-time quaking-induced conversion (RT-QuIC), we found that formic acid treatment reduced α-syn seeding dose (picograms of α-syn seeds per ml of brain homogenate) in DLB and mouse brain by 6 and 8 logarithms, respectively. RT-QuIC reactions seeded with formic acid-treated brain homogenates showed significantly longer lag phase, and decreased total thioflavin T fluorescence compared to untreated samples, indicating that formic acid treatment impairs the ability of pathological α-syn to seed monomeric α-syn. Importantly, the α-syn pathologic features and the immunostaining quality were preserved in formic acid-treated tissues. Our results demonstrate that formic acid treatment is a quick and efficient procedure for reducing α-syn seeding activity in fixed brain samples, thereby lowering the risk of accidental exposure in laboratories without compromising the quality of histopathological analysis.
Summary: Formic acid treatment drastically reduces α -synuclein seeding activity in fixed human and mouse brain samples while preserving histopathological quality.

DOI: https://doi.org/10.1101/2025.07.14.664807
Int J Mol Sci. 2025 Jul 25. pii: 7205. [Epub ahead of print]26(15):

Development and Characterization of a Novel α-Synuclein-PEST H4 Cell Line for Enhanced Drug Screening in α-Synucleinopathies.

Nancy Carullo, Viktor Haellman, Simon Gutbier, Sonja Schlicht, Thien Thuong Nguyen, Rita Blum Marti, Philippe Hartz, Lothar Lindemann, Lina Schukur.

  Alpha-Synuclein (α-Syn) is a presynaptic neuronal protein implicated in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies, primarily through its aggregation into insoluble fibrils. The extended α-Syn half-life necessitates treatment durations that are incompatible with efficient high-throughput drug screening, can risk compound stability or cause cellular toxicity. To address this, we inserted a PEST sequence, a motif known to promote rapid protein degradation, at the C-terminus of the SNCA gene using CRISPR/Cas9 to create a novel cell line with reduced α-Syn half-life. This modification accelerates α-Syn turnover, providing a robust model for studying α-Syn dynamics and offering a platform that is applicable to other long-lived proteins. Our results demonstrate a six-fold reduction in α-Syn half-life, enabling the rapid detection of changes in protein levels and facilitating the identification of molecules that modulate α-Syn production and degradation pathways. Using inhibitors of the proteasome, transcription, and translation further validated the model's utility in examining various mechanisms that impact protein levels. This novel cell line represents a significant advancement for studying α-Syn dynamics and offers promising avenues to develop therapeutics for α-synucleinopathies. Future research should focus on validating this model in diverse experimental settings and exploring its potential in high-throughput screening applications.

Keywords:  PEST sequence; Parkinson’s disease; cell engineering; drug screening; protein degradation; protein turnover; synucleinopathies; α-synuclein

DOI:  https://doi.org/10.3390/ijms26157205
Nat Rev Neurol. 2025 Aug 11.

Advances in PET imaging of protein aggregates associated with neurodegenerative disease.

Makoto Higuchi, Kenji Tagai, Keisuke Takahata, Hironobu Endo.

Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public-private partnerships focused on biomarker development.

DOI: https://doi.org/10.1038/s41582-025-01126-2
Mol Neurobiol. 2025 Aug 16.

Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?

Ashi Mannan, Akhil Sharma, Thakur Gurjeet Singh.

  The ubiquitin-proteasome system (UPS) plays a critical role in protein homeostasis within eukaryotic cells. This review article examines the UPS's role in neuronal morphology and neurodegeneration through systematic analysis of current research. In neurodegenerative disorders (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), UPS dysfunction contributes significantly to pathogenesis through accumulation of ubiquitinated misfolded proteins, disruption of cellular proteostasis, impaired substrate ubiquitination, and proteasomal deterioration. The UPS maintains normal central nervous system (CNS) function by regulating protein degradation. When this system fails, cellular proteostasis becomes compromised, accelerating neurodegeneration. Recent research has identified potential interventions for UPS activation through genetic modification and synthetic compounds. This review assesses how specific UPS components could serve as pharmacological targets for treating NDDs. By modulating UPS-mediated genes and pathways, novel therapeutic strategies may emerge for conditions including AD, PD, HD), and ALS. Current evidence suggests the UPS represents a promising therapeutic target for addressing the fundamental protein homeostasis disruptions underlying these devastating neurological conditions. Targeting this system could potentially slow disease progression by restoring proper protein degradation mechanisms and preventing toxic protein accumulation characteristic of NDDs.

Keywords:  Alzheimer’s disease (AD); Amyotrophic lateral sclerosis (ALS); Huntington disease (HD); Neurodegenerative disorders (NDDs); Parkinson’s disease (PD); Ubiquitin–proteasome system (UPS)

DOI:  https://doi.org/10.1007/s12035-025-05263-z
Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2508403122

Client-scaffold interactions suppress aggregation of a client protein in model condensates.

Rashik Ahmed, Rhea P Hudson, Julie D Forman-Kay, Lewis E Kay.

  Many studies have shown that sequestration of client proteins into condensates locally increases their concentrations and/or modulates their conformational landscapes to promote aberrant aggregation. Far fewer examples have emerged where the proteinaceous condensed phase environment protects clients from aggregation. Here, we show that a condensate scaffolded by the C-terminal disordered region of Cell Cycle Associated Protein 1 (CAPRIN1) suppresses aggregation of the Fused in Sarcoma (FUS) RNA Recognition Motif (RRM) client, both components of stress granules. Although FUS RRM aggregation is mediated through the unfolded ensemble, comparative NMR studies of the FUS RRM outside and within the condensate establish that CAPRIN1 condensates attenuate FUS RRM aggregation despite locally increasing its concentration by twofold and significantly unfolding the domain. Regions of transient intermolecular contacts between unfolded FUS RRM protomers that could drive aggregation have been identified, including the hydrophobic segments spanning I287-I308 and G335-A369. Intermolecular NOE experiments recorded on the FUS RRM:CAPRIN1 condensate indicate that CAPRIN1 interacts with much of the unfolded FUS RRM, with regions of stronger contacts including the RRM sequences 287IFVQ290, 296VTIES300, 322INLY325, and 351IDWFDG356. These interactions collectively outcompete the homotypic contacts between unfolded FUS RRM clients driving aggregation. Our results demonstrate that condensate scaffold molecules can, in some cases, shield client interprotomer interactions, delaying or completely suppressing their aggregation.

Keywords:  CAPRIN1; FUS RRM; NMR spectroscopy; phase separation; protein free energy landscape

DOI:  https://doi.org/10.1073/pnas.2508403122
NPJ Parkinsons Dis. 2025 Aug 11. 11(1): 236

Strain-specific effects of Desulfovibrio on neurodegeneration and oxidative stress in a Caenorhabditis elegans PD model.

Khosrow Mohammadi, Dongming Zhang, Per Erik Joakim Saris.

The gut microbiota is increasingly recognized as a key contributor to intestinal and brain pathologies, including Parkinson's disease (PD). Sulfate-reducing Desulfovibrio (DSV) species have emerged as microbial drivers through hydrogen sulfide and other neurotoxic factors. Using the Caenorhabditis elegans PD model NL5901 expressing human α-synuclein, we examined the effects of six DSV strains from human, animal, and environmental sources on food preference, α-syn aggregation, ROS production, gene expression, and lifespan. C. elegans strongly preferred environmental strains, particularly D. vulgaris DSM 644 (94.7% vs. 5.3% over D. piger DSM 749). In contrast, the animal isolate D. desulfuricans DSM 6949 and PD isolate D. spp. MUU 26 induced the highest α-syn aggregation (49.05 and 40.15 aggregates), ROS (3.42-fold, 3.01-fold), and sod-3, daf-16, and hsp-16.1 repression. DSM 644-fed worms exhibited a protective transcriptional profile and the greatest lifespan extension (median 36 days). These results highlight strain-specific effects of DSV on neurodegeneration, oxidative stress, and aging, reinforcing the need for mechanistic validation in mammalian PD models.

DOI: https://doi.org/10.1038/s41531-025-01102-z
Acta Neuropathol Commun. 2025 Aug 09. 13(1): 169

Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.

Muzi Du, Suleyman C Akerman, Charlotte M Fare, Linhao Ruan, Svetlana Vidensky, Lyudmila Mamedova, Katie Koo, Joshua Lee, Jeffrey D Rothstein.

  TMEM106B is a lysosome/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of the endogenous TMEM106B protein in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy using an extensively validated TMEM106B antibody. We found profound correlations between the endogenous TMEM106B protein with known TDP-43 and tau pathology in murine models of C9-ALS/FTD and tauopathy, respectively. By using an antibody previously shown to recognize the pathologic TMEM106B C-terminal fragments, we then performed a similar analysis on postmortem brain tissues from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). Convergent evidence from both murine models and human patients links TMEM106B to TDP-43 nuclear clearance at the cellular level in C9-ALS. By characterizing endogenous TMEM106B in mice and human postmortem tissue, our work reveals essential considerations that must be taken when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Frontotemporal dementia; Murine models of neurodegenerative disease; Neurodegenerative disease; Pathology; TAR DNA-binding protein 43; TMEM106B; Tauopathy

DOI:  https://doi.org/10.1186/s40478-025-02087-9
J Biomol Struct Dyn. 2025 Aug 16. 1-24

Amino acid osmolytes disrupting intradomain interactions reduce the amyloidogenicity of α-synuclein: studies with charged l-amino acids and their derivatives.

Archi Saurabh, Suraj Chauhan, Jogadhenu S S Prakash, N Prakash Prabhu.

  Aggregation of α-synuclein (α-syn) is a hallmark of Parkinson's and dementia with Lewy bodies pathogenesis. The high plasticity and lack of stable tertiary structure make α-syn more susceptible to its surrounding environment. Under stress conditions, small organic molecules known as osmolytes accumulate inside the cells. They affect the conformational states and fibrillation pathways of proteins. Here, the effects of eight different amino acid osmolytes (charged: l-glutamate, l-aspartate, l-lysine, l-arginine; amide side chains: l-glutamine, l-asparagine; and N-acetylated: N-acetyl-l-glutamic acid, N-acetyl-l-lysine) on the fibrillation of human α-synuclein were examined. Arginine and N-acetyl-l-lysine inhibited the fibrillation at concentrations above 0.2 and 0.4 M, respectively. Lysine, asparagine, and glutamate accelerated the fibrillation by reducing lag time. N-acetyl-l-glutamic acid induced lag-independent fibrillation, whereas glutamine and asparagine showed concentration-dependent effects on the fibrillation with reduced lag time at higher concentrations. Molecular dynamics simulations revealed that interdomain contacts facilitated the fibrillation. The amino acids interacting predominantly through van der Waals interactions reduced the lag time of α-syn. However, the amino acids having strong electrostatic interactions with the protein disrupted intradomain contacts, favored extended conformation, and inhibited the fibril formation.

Keywords:  amino acids; fibril formation; fibril inhibition; intrinsically disordered protein; molecular dynamics simulation; organic osmolytes; α-Synuclein

DOI:  https://doi.org/10.1080/07391102.2025.2543362
Acta Neuropathol. 2025 Aug 13. 150(1): 19

Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology.

Toru Yamashita, Osamu Yokota, Daiki Ousaka, Hongming Sun, Takashi Haraguchi, Ricardo Satoshi Ota-Elliott, Chika Matsuoka, Tomohito Kawano, Hanae Nakashima-Yasuda, Yusuke Fukui, Yumiko Nakano, Ryuta Morihara, Masato Hasegawa, Yasuyuki Hosono, Seishi Terada, Manabu Takaki, Hiroyuki Ishiura.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in DNAJC7, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in DNAJC7 expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, DNAJC7 knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas DNAJC7 overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, dnajc7 knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in DNAJC7 to familial ALS with TDP-43 pathology.

Keywords:   DNAJC7 ; Amyotrophic lateral sclerosis; Heat shock protein; Live-cell imaging; TDP-43; Zebrafish disease model

DOI:  https://doi.org/10.1007/s00401-025-02899-y
Redox Biol. 2025 Aug 10. pii: S2213-2317(25)00330-1. [Epub ahead of print]86 103817

α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.

Plamena R Angelova, Noemi Esteras, James Evans, Marko Kostic, Ronald Melki, Jochen H M Prehn, Sonia Gandhi, Andrey Y Abramov.

  One of the major histopathological features of Parkinsons's disease - intracellular Lewy bodies - consists of misfolded α-synuclein. This protein can self-assemble, spread through the brain and seed its own aggregation. Aggregated α-synuclein is shown to induce mitochondrial dysfunction that leads to neuronal loss. Using human iPSC-derived SNCA triplication (3xSNCA) and isogenic control (ISO) neurons we studied whether acute exposure to fibrillar α-synuclein, or its seeding properties, induce effects on mitochondrial function and toxicity. Chronic exposure of neurons to fibrillar α-synuclein (up to 3 weeks) induces a gradual increase of endogenous α-synuclein seeding in neurons, with a decrease in the exogenous fibrillar α-synuclein in ISO and 3xSNCA neurons. Application of exogenous fibrillar α-synuclein induced mitochondrial depolarisation, impairment of complex I function, increased ROS production, oxidative stress and cell death. Notably, α-synuclein seeding following weeks of incubation almost completely restored mitochondrial function and redox balance of human neurons. Thus, mitochondrial dysfunction and oxidative stress in human neurons can be induced acutely only by transient exogenous fibrillar α-synuclein, but seeding is irrelevant to long-term mitochondrial dysfunction or toxicity. This study also indicates an acute, transient toxic insult followed by a remarkable period of adaptation and functional recovery, highlighting the resilience of human neurons.

Keywords:  Neurotoxicity; Parkinson's disease; Seeding; Snca; α-synuclein

DOI:  https://doi.org/10.1016/j.redox.2025.103817
Nat Chem. 2025 Aug 14.

High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs.

Emma C Carroll, Hyunjun Yang, Wyatt C Powell, Annemarie F Charvat, Abby Oehler, Julia G Jones, Kelly M Montgomery, Anthony Yung, Zoe Millbern, Alexander I P Taylor, Martin Wilkinson, Neil A Ranson, Sheena E Radford, Nelson R Vinueza, William F DeGrado, Daniel A Mordes, Carlo Condello, Jason E Gestwicki.

Aggregation of microtubule-associated protein tau into conformationally distinct fibrils underpins neurodegenerative tauopathies. Fluorescent probes (fluoroprobes) such as thioflavin T have been essential tools for studying tau aggregation; however, most of them do not discriminate between amyloid fibril conformations (polymorphs). This gap is due, in part, to a lack of high-throughput methods for screening large, diverse chemical collections. Here we leverage advances in protein-adaptive differential scanning fluorimetry to screen the Aurora collection of 300+ fluoroprobes against multiple synthetic fibril polymorphs, including those formed from tau, α-synuclein and islet amyloid polypeptide. This screen-coupled with excitation-multiplexed bright-emission recording (EMBER) imaging and orthogonal secondary assays-revealed pan-fibril-binding chemotypes, as well as fluoroprobes selective for fibril subsets. One fluoroprobe recognized tau pathology in ex vivo brain slices from Alzheimer's disease and rodent models. We propose that these scaffolds represent entry points for developing fibril-selective ligands.

DOI: https://doi.org/10.1038/s41557-025-01889-7
Protein Sci. 2025 Sep;34(9): e70267

N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo state.

Kristine Steen Jensen.

  Co- and post-translational modifications can significantly impact the structure, dynamics, and function of proteins. In this study, we investigate how N-terminal acetylation affects misfolding and self-assembly of the enzyme superoxide dismutase 1 (SOD1), implicated in amyotrophic lateral sclerosis (ALS). Studies of protein inclusions in patient samples and animal models have shown that wild-type SOD1 can form amyloid fibrils even when no mutations are found in the sod1 gene. This has identified SOD1 amyloid formation as a possible common denominator of ALS and may suggest that co- and post-translational modifications, like N-terminal acetylation found in human SOD1, can be a factor in disease development. In this work, the impact of N-terminal acetylation of SOD1 on stability and aggregation is characterized. Results show that the structure and thermal stability of the apo state are unaffected by the modification while the amyloid formation rate is significantly enhanced. This is caused by a shortening of the nucleation phase together with an increase of fibril elongation by more than 10-fold upon N-terminal acetylation of SOD1. Collectively, the findings demonstrate how regulation by co- and post-translational modifications can influence protein misfolding and self-assembly.

Keywords:  N‐terminal acetylation; amyloid formation kinetics; amyotrophic lateral sclerosis; post‐translational modification; superoxide dismutase 1

DOI:  https://doi.org/10.1002/pro.70267
J Biol Chem. 2025 Aug 13. pii: S0021-9258(25)02445-7. [Epub ahead of print] 110594

Mechanism of inhibition of acid-mediated transthyretin aggregation by designed peptides.

Xun Sun, Rose Pedretti, H Jane Dyson, Lorena Saelices, Peter E Wright.

  Aggregation of transthyretin (TTR) causes TTR cardiomyopathy and polyneuropathy through amyloidosis. To initialize TTR aggregation, the native TTR tetramer first dissociates to a monomeric intermediate, which misfolds and self-assembles to oligomers, eventually forming insoluble aggregates and fibrils. Peptide inhibitors have been designed to cap two β-strands that are buried in the well-folded tetramer but are solvent-exposed in the monomeric aggregation intermediate. However, how these peptides affect the reaction kinetics of individual steps in the multi-step TTR aggregation pathway remains unknown. Here, we integrated 19F-NMR and kinetic modeling to determine aggregation reaction rates of individual steps with the peptide inhibitors and extract the free energy landscape along the TTR aggregation pathway. We found direct kinetic evidence that the peptide inhibitors bind to monomeric intermediates and misfolded tetramers at acidic pH, but do not bind to structured TTR monomers or tetramers at neutral pH. In addition, the peptides do not bind to amorphous aggregates formed at acidic pH and physiological temperature in vitro, in contrast to the previously reported findings that these peptides recognize ex vivo TTR fibrils derived from patients with TTR amyloidosis. Interestingly, the peptides bind to soluble oligomers formed at acidic pH and low temperature in vitro, suggesting that these oligomers may share structural similarity with misfolded monomeric intermediates and patient-derived TTR fibrils. Our methods provide quantitative and mechanistic details for peptide-inhibited TTR aggregation.

Keywords:  aggregation inhibitor; aggregation kinetics; aggregation mechanism; amyloid; real-time (19)F-NMR; transthyretin aggregation

DOI:  https://doi.org/10.1016/j.jbc.2025.110594
Neural Regen Res. 2025 Aug 13.

Nigrostriatal dopaminergic vulnerability in Parkinson's disease: Neuroprotective strategies.

Estefanía Santana-Román, Luis O Soto-Rojas, Elias Manjarrez, Oscar Arias-Carrión.

  The selective vulnerability of nigrostriatal dopaminergic neurons is a hallmark of Parkinson's disease and underlies its progressive motor decline. These neurons are uniquely susceptible to degeneration due to their extensive axonal arborization, high energy demands, sustained pacemaking activity, and cytosolic dopamine metabolism, which collectively promote oxidative stress and mitochondrial dysfunction. Advances in single-nucleus RNA sequencing and spatial transcriptomics have revealed transcriptionally distinct dopaminergic subtypes within the human substantia nigra pars compacta, such as AGTR1 + /SOX6 + and RIT2 + populations, which exhibit subtype-specific transcriptional stress signatures and are preferentially lost in Parkinson's disease. These findings underscore the role of intrinsic vulnerability, influenced by genetic risk loci, mitochondrial stress, and protein misfolding pathways, including α-synuclein aggregation. Furthermore, neuroinflammation, iron accumulation, and vascular dysfunction act synergistically to amplify neuronal loss. This review integrates molecular, cellular, and systems-level mechanisms contributing to dopaminergic degeneration and evaluates emerging neuroprotective strategies. These include anti-oxidative, anti-inflammatory, mitochondrial therapies, novel biomarkers, gene editing, and cell replacement techniques. Understanding the selective vulnerability of nigrostriatal subtypes offers a promising path toward precision-targeted, disease-modifying treatments for Parkinson's disease.

Keywords:  Parkinson's disease; dopamine metabolism; dopaminergic neurons; iron accumulation; neurodegeneration; neurovascular factors; nigrostriatal pathway; oxidative stress; plasticity; α-synuclein

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00380
Gene. 2025 Aug 13. pii: S0378-1119(25)00511-6. [Epub ahead of print] 149722

Neuroprotective mechanism of LincRNA in neurodegenerative diseases.

Yizhou Lin, Jiarui Wang, Bowen Liu, Tianye Hu, Jianlan Gu.

  Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal dysfunction and cell death associated with protein aggregation, mitochondrial dysfunction, and neuroinflammation. Since the precise pathogenesis of NDs remains unclear, current therapeutic options are limited to symptomatic relief with minimal disease-modifying effects. Emerging evidences highlight the critical regulatory roles of long non-coding RNAs (lncRNAs) in the onset and progression of NDs through epigenetic modulation, mRNA stability control, and protein scaffolding. Among these, long intergenic non-coding RNAs (lincRNAs) have attracted significant attention for their dual roles in neuroprotection and neurodegeneration. These lincRNAs modulate disease-related genes through chromatin remodeling, miRNA sponging, and stress granule formation. This review systematically analyzes lincRNA expression signatures across NDs, their mechanistic roles in protein homeostasis, and emerging therapeutic strategies including antisense oligonucleotides and CRISPR-based approaches.

Keywords:  Long intergenic non-coding RNA (lincRNA); Neurodegenerative disease; Neuroprotection

DOI:  https://doi.org/10.1016/j.gene.2025.149722
Behav Brain Res. 2025 Aug 12. pii: S0166-4328(25)00362-6. [Epub ahead of print]495 115775

DJ-1 in Parkinson's disease: Its important role at endoplasmic reticulum-mitochondria contact sites.

Haohao Fan, Yuanyuan Li, Juan Huang, Jinyu Jiang, Fei Feng, Nanqu Huang, Yong Luo.

  Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions of people globally and causing significant impairments in motor and cognitive functions. The key pathological hallmarks of PD include the aggregation of α-synuclein (α-Syn), degeneration of dopaminergic neurons, and formation of Lewy bodies (LBs), leading to a range of clinical symptoms, such as rigidity, bradykinesia, and cognitive deficits. Although the exact causes of PD are not fully understood, factors such as oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress are implicated in its pathogenesis. The protein DJ-1 (PARK7), a highly conserved antioxidant, has been identified as a significant factor in PD, particularly because of its role in maintaining cellular homeostasis and regulating cellular responses to stress. The interaction of DJ-1 with endoplasmic reticulum-mitochondria contact sites (MERCs) is crucial for calcium regulation, autophagy, and the management of ER stress, all of which are related to PD progression. This review focuses on the function of DJ-1 within mitochondria-associated endoplasmic reticulum membranes (MAMs or ER-MAMs), aiming to provide insights into PD mechanisms and potential therapeutic targets.

Keywords:  DJ-1; Endoplasmic reticulum; Mitochondria; Mitochondria-associated endoplasmic reticulum membranes; Mitochondria-associated membranes; Parkinson's disease

DOI:  https://doi.org/10.1016/j.bbr.2025.115775