bims-proned 2025-08-24 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–08–24
twelve papers selected by
Verena Kohler, Umeå University

Influence of palmitoylation in axonal transport mechanisms in neurodegenerative diseases.
cnnm-5 knockdown improves proteostasis of mutant Huntingtin protein in C. elegans.
Hydrophobic residues in the α-synuclein NAC domain drive seed-competent fibril formation and are targeted by peptide inhibitors.
The Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation.
Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria.
Nuclear pore complex dysfunction drives TDP-43 pathology in ALS.
A role for the autophagy receptor NBR1 in the degradation of tau aggregates.
CD11b Activation Reduces Myeloid Brain Infiltration and Mitigates Synucleinopathy in a Model of Parkinson's Disease.
Proteostasis and Unfolded Protein Response Dynamics in Human Neuron and Mouse Glia Co-culture Reveal Cell-Specific Aging Responses.
A brain-derived tau oligomer polymorph is associated with cognitive resilience to Alzheimer's disease.
A Slower-Progressing TDP-43 rNLS8 Mouse Model for ALS: Implications for Preclinical and Mechanistic Studies.
Discovery of oleanolic acid derivatives that inhibit tau protein phosphorylation and neuroinflammation induced by Aβ25-35 in vitro and in vivo.

Front Cell Neurosci. 2025 ;19 1613379

Influence of palmitoylation in axonal transport mechanisms in neurodegenerative diseases.

Praveen B S, Priti Talwar.

  Progressive functional loss and death of neurons are characteristics of neurodegenerative diseases such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). These diseases are often linked with disruptions in axonal transport and synaptic functions. Accumulation of misfolded proteins is observed as a commonly shared pathology for these diseases, where aberrant accumulation of amyloid beta (Aβ), tau, α-synuclein (α-syn) and TAR DNA-binding protein 43 (TDP-43), are found in AD, PD and ALS, respectively. These accumulations are observed to be involved in disrupting axonal transport and compromising neuronal survival. Axonal transport is an essential process where proper functioning of the transport mechanism is important for maintaining neuronal hemostasis by transporting of proteins, organelles and neurotransmitter complexes. This review explores the role of palmitoylation in regulating neuronal axonal transport and their impact on other neuronal functions along with neurodegeneration mechanisms. Palmitoylation is a reversible lipid modification, which is widely studied second to phosphorylation. Enzymes like palmitoyl acyltransferases and acyl-protein thioesterases are responsible for attachment and detachment of palmitic acid causing palmitoylation and depalmitoylation of neuronal proteins. In axonal transport, palmitoylation influences the localization and functioning of the proteins, which connectively plays a role in synaptic stability by interacting with synaptic scaffolding proteins and neurotransmission receptors.

Keywords:  axonal transport; depalmitoylation; neurodegenerative diseases; palmitoylation; zDHHC

DOI:  https://doi.org/10.3389/fncel.2025.1613379
MicroPubl Biol. 2025 ;2025

cnnm-5 knockdown improves proteostasis of mutant Huntingtin protein in C. elegans.

Matthew Hull, Joslyn Mills.

Huntington's disease (HD) is an age-related neurodegenerative disease associated with the aggregation of mutant Huntingtin protein (mHTT). It is theorized that prevention or clearance of these aggregates through autophagy and the ubiquitin proteasome system (UPS) protects neurons from degeneration. Using a C. elegans model of HD, a small reverse genetic screen of 100 random genes on Chromosome 3 identified cnnm-5 as a genetic modifier of mHTT accumulation. During development, loss of cnnm-5 by RNAi ( cnnm-5 i) protects against mHTT accumulation, implicating cnnm-5 as a negative regulator of protein aggregation prevention or clearance. Here we report that knocking down cnnm-5 leads to decreased mHTT protein aggregation through the upregulation of the UPS and autophagy pathways, leading to increased lifespan. Further experimentation using a nematode model of Alzheimer's disease demonstrates cnnm-5 i protects against paralysis by decreasing beta amyloid protein misfolding in body wall muscles.

DOI: https://doi.org/10.17912/micropub.biology.001497
FEBS J. 2025 Aug 17.

Hydrophobic residues in the α-synuclein NAC domain drive seed-competent fibril formation and are targeted by peptide inhibitors.

Viswanath Das, Sayed Mostafa Modarres Mousavi, Narendran Annadurai, Sunčica Sukur, Faramarz Mehrnejad, Sajad Moradi, Lukáš Malina, Markéta Kolaříková, Vaclav Ranc, Ivo Frydrych, Roman Kouřil, Saman Hosseinkhani, Marián Hajdúch, Maryam Nikkhah.

  Alpha-synuclein (αSyn) is a 14-kDa intrinsically disordered protein that aggregates into insoluble fibrils in synucleinopathies, including Lewy bodies, multiple system atrophy, and Parkinson's disease, contributing to neurotoxicity and disease progression. The ability of these fibrils to seed further aggregation of native protein is central to αSyn pathology. Here, we examined the broader non-amyloid component (NAC) domain, focusing on how residues flanking the hydrophobic 68-71 (GAVV) motif of αSyn (residues 8-11 in NAC35) modulate nucleation, stability, and pathological seeding. Using full-length NAC peptide and truncated variants, we show that the 68-71 (GAVV) stretch is critical for nucleation and aggregation into prion-like fibrils. Peptide inhibitors targeting this hydrophobic region block the formation of seed-competent fibrils. Molecular dynamics simulations showed that these inhibitors alter peptide-peptide interactions and contact key hydrophobic residues within the NAC domain. Further analysis indicates that residues beyond the 68-71 (GAVV) motif, such as 79-95, are critical for stabilizing fibrils and promoting seeding competency. Peptide B interactions with key hydrophobic motifs within the NAC domain were visualized in silico, offering mechanistic insights into how it disrupts aggregation.

Keywords:  Parkinson's disease; alpha‐synuclein; amyloid fibril; hydrophobic region; non‐amyloid component; peptide inhibitor; synuclein seeding

DOI:  https://doi.org/10.1111/febs.70222
bioRxiv. 2025 Aug 12. pii: 2025.08.10.669490. [Epub ahead of print]

The Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation.

Biswarathan Ramani, Kean Ehsani, Martin Kampmann.

Polyglutamine (polyQ) diseases, including Huntington's disease and several spinocerebellar ataxias, are caused by abnormally expanded CAG nucleotide repeats, which encode aggregation-prone polyQ tracts. Substantial prior evidence supports a pathogenic role for polyQ protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. In this study, we developed a FRET-based reporter system that models polyQ aggregation in human cells and used it to perform a high-throughput CRISPR interference screen targeting all known molecular chaperones. This screen identified as a strong suppressor of polyQ aggregation the Hsp40 co-chaperone DNAJC7, which has previously been shown to modify aggregation of other disease proteins (tau and TDP-43) and has mutations causative for amyotrophic lateral sclerosis. We validated this phenotype and further established a physical interaction between DNAJC7 and polyQ-expanded protein. In contrast, DNAJC7 did not modify aggregation of polyglycine (polyG) in a FRET-based model of neuronal intranuclear inclusion disease. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating folding of disease-associated proteins.

DOI: https://doi.org/10.1101/2025.08.10.669490
Nat Commun. 2025 Aug 16. 16(1): 7651

Alpha-synuclein interacts with regulators of ATP homeostasis in mitochondria.

Tetiana Serdiuk, Yanick Fleischmann, Dhiman Ghosh, Aro Delparente, Viviane Reber, Larissa Frey, David Rhyner, Juan Gerez, Norbert Volkmar, Lucie Kralickova, Guillaume Mas, Christian Dörig, Sebastian Hiller, Roger Schibli, Linjing Mu, Paola Picotti, Roland Riek.

Mitochondrial dysfunction and accumulation of α-synuclein aggregates are hallmarks of the neurodegenerative Parkinson's disease and may be interconnected. To investigate the interplay between α-synuclein and brain mitochondria at near atomic structural level, we apply NMR and identify α-synuclein protein interactors using limited proteolysis-coupled mass spectrometry (LiP-MS). Several of the proteins identified are related to ATP synthesis and homeostasis and include subunits of ATP synthase and the adenylate kinase AK2. Furthermore, our data suggest that α-synuclein interacts with the Parkinson's disease-related protein DJ1. NMR analysis demonstrates that both AK2 and DJ1 bind to the C-terminus and other segments of α-synuclein. Using a functional assay for AK2, we show that monomeric α-synuclein has an activating effect, whereas C-terminally truncated α-synuclein and α-synuclein in an amyloid fibrillar state have no significant effect on AK2 activity. Our results suggest that α-synuclein modulates ATP homeostasis in a manner dependent on its conformation and its C-terminal acidic segment.

DOI: https://doi.org/10.1038/s41467-025-62895-4
Redox Biol. 2025 Aug 14. pii: S2213-2317(25)00337-4. [Epub ahead of print]86 103824

Nuclear pore complex dysfunction drives TDP-43 pathology in ALS.

O Ramírez-Núñez, S Rico-Ríos, P Torres, V Ayala, A Fernàndez-Bernal, M Ceron-Codorniu, P Andrés-Benito, A Vinyals, S Maqsood, I Ferrer, R Pamplona, M Portero-Otin.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and pathological aggregation of TDP-43. While protein misfolding and impaired autophagy are established features, accumulating evidence highlights the nuclear pore complex (NPC)as a vulnerable, redox-sensitive hub in ALS pathogenesis. Here, we show that selective loss of NPC components, particularly the scaffold proteins NUP107 and NUP93, and FG-repeat-containing components-is a consistent finding across ALS postmortem spinal cord, SOD1^G93A and TDP-43 mutant mouse models, and human cell systems.CRISPR-mediated depletion of NUP107 in human cells triggers hallmark features of ALS pathology, including cytoplasmic TDP-43 mislocalization, increased phosphorylation, and autophagy dysfunction. Conversely, TDP-43 knockdown perturbs NPC composition, suggesting a reciprocal regulatory loop. Crucially, we demonstrate that oxidative stress exacerbated NPC subunit mislocalization and enhanced TDP-43 aggregation. Using oxime blotting and DNPH assays, we show that FG-repeat subunits of NPC were direct targets of redox-driven carbonylation, indicating that oxidative modifications compromise NPC integrity thuspotentially affecting nucleocytoplasmic transport. Our findings established NPC dysfunction as a redox-sensitive driver of TDP-43 pathology in ALS and highlight nucleocytoplasmic transport as a promising therapeutic axis. The susceptibility of long-lived NPC proteins to oxidative damage provides a mechanistic link between redox stress, proteostasis collapse, and neurodegeneration.

DOI: https://doi.org/10.1016/j.redox.2025.103824
Neurobiol Dis. 2025 Aug 14. pii: S0969-9961(25)00276-1. [Epub ahead of print]214 107060

A role for the autophagy receptor NBR1 in the degradation of tau aggregates.

Marie Neu, Iwan Parfentev, Gregory K Potts, Nina Stöberl, Jürgen Korffmann, Andreas Striebinger, Daniela Geist, Dimitris Papageorgiou, Hanna Tarhonskaya, Nicholas McKitterick, Jeroen van Bergeijk, Christopher Untucht, Peter Reinhardt, Jon D Williams, Michaela J Heimann, Laura Gasparini, Dagmar E Ehrnhoefer.

  Neurofibrillary tangles (NFTs), comprising hyperphosphorylated and aggregated Tau protein, are a primary neuropathological feature of Alzheimer's Disease (AD). In patients, the formation and spread of NFTs across the brain correlate with cognitive decline. However, the mechanisms driving Tau aggregation and leading to the subsequent neuronal dysfunction are not fully understood. In this study, we explored proteomic and phosphoproteomic changes resulting from the seed-induced aggregation of endogenous Tau in human neurons, derived from induced pluripotent stem cells (iPSCs). We discovered previously undescribed phosphorylation sites on NBR1, an autophagy receptor, which were significantly altered by Tau aggregation in vitro. We further show that NBR1 directly interacts with phosphorylated Tau and Tau aggregates in various cellular models. This interaction is associated with autophagic Tau degradation in HEK biosensor cells, and siRNA-mediated knockdown of NBR1 significantly increases Tau aggregate levels in iPSC-derived neurons. Additionally, we find that NBR1 expression is significantly increased in AD patients, and it specifically interacts with Tau in human AD brain, underscoring the relevance of our findings to the human disease. These insights provide a deeper understanding of the molecular interactions between autophagy receptors and Tau pathology in AD and reveal a role for NBR1 as an important receptor for pathological forms of Tau.

Keywords:  Alzheimer's disease; Autophagy receptor; Mass spectrometry; Phosphoproteomics; Proteomics; Tau aggregation; iPSC-derived neurons

DOI:  https://doi.org/10.1016/j.nbd.2025.107060
bioRxiv. 2025 Aug 15. pii: 2025.08.11.669712. [Epub ahead of print]

CD11b Activation Reduces Myeloid Brain Infiltration and Mitigates Synucleinopathy in a Model of Parkinson's Disease.

Ameera M Shaw, Viviana Jimenez, Billy Nguyen, Jayda Duvernay, Solji Choi, Mike Cameron, Bryan A Killinger, Vineet Gupta.

The pathology of Parkinson's disease is defined by α-synuclein (α-syn) aggregation into neuronal Lewy bodies, which may lead to chronic neuroinflammation and dopaminergic neurodegeneration. Misfolded α-syn activates Toll-like receptor signaling in microglia, leading to downstream activation of NF-κB and subsequent release of pro-inflammatory cytokines. These cytokines recruit pro-inflammatory myeloid cells from circulation, thereby amplifying neuroinflammation. Thus, reducing microglial activation and myeloid cell infiltration has the potential to reduce neuroinflammation and PD pathology. Here, we investigated a targeted immunomodulatory strategy using LA1, a novel, small-molecule agonist of CD11b, a β2 integrin receptor highly and selectively expressed on myeloid cells and microglia. CD11b has key roles in cell adhesion, migration, and phagocytosis. Previous work has demonstrated that CD11b agonism via LA1 transiently enhances integrin-mediated adhesion that limits immune cell transmigration and tissue infiltration. CD11b agonism also suppresses TLR-driven inflammatory signaling and myeloid cell activation. To evaluate its efficacy in vivo , we utilized pre-clinical Parkinson's disease model by stereotaxically delivering AAV2-SYN to induce α-synuclein overexpression in the murine midbrain. Mice were treated with oral LA1 for four or eight weeks and analyzed. LA1 treatment significantly reduced microglial activation and decreased brain infiltration of peripheral immune cells, thereby attenuating α-synuclein-induced neuroinflammation. These findings suggest that CD11b agonism may offer a dual-action therapeutic approach in Parkinson's disease by dampening pro-inflammatory responses by central and peripheral myeloid cells.

DOI: https://doi.org/10.1101/2025.08.11.669712
bioRxiv. 2025 Aug 13. pii: 2025.08.11.669714. [Epub ahead of print]

Proteostasis and Unfolded Protein Response Dynamics in Human Neuron and Mouse Glia Co-culture Reveal Cell-Specific Aging Responses.

Lea A Barny, Sarah K Garcia, Aiden J Houcek, Burak Uzay, Minsoo Kim, Ege T Kavalali, Lars Plate.

Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development, maturation, and aging. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to investigate cell type- specific, age-related changes in the proteostasis network using data-independent acquisition (DIA) LC-MS/MS proteomics. We quantified branch-specific unfolded protein response (UPR) activation by monitoring curated effector proteins downstream of the ATF6, IRE1/XBP1s, and PERK pathways, enabling a comprehensive, unbiased evaluation of UPR dynamics during neuronal aging. Species-specific analysis revealed that aging neurons largely preserved proteostasis, although they showed some signs of collapse, primarily in ER-to-Golgi transport mechanisms. However, these changes were accompanied by upregulation of proteostasis-related machinery and activation of the ATF6 branch, as well as maintenance of the XBP1s and PERK branches of the UPR with age. In contrast, glia exhibited broad downregulation of proteostasis factors and UPR components, independent of neuronal presence. Furthermore, we quantified stimulus-specific modulation of select UPR branches in aged neurons exposed to pharmacologic ER stressors. These findings highlight distinct, cell-type-specific stress adaptations during aging and provide a valuable proteomic resource for dissecting proteostasis and UPR regulation in the aging brain.
Significance: Understanding how the unfolded protein response (UPR) and proteostasis network change with age is often studied in model organisms, where pathways are assessed across mixed cell types. Such systems can obscure cell-type-specific regulation. Here, we evaluate age-associated remodeling of the UPR and proteostasis network in a dual-species co-culture of human neurons and mouse glia using DIA proteomics. This approach enables species-specific proteomic profiling without physical separation, supported by a customizable data analysis pipeline. We show that neurons and glia exhibit divergent age-related responses, with neurons maintaining adaptive proteostasis and glia showing broader declines. The analytical framework presented here supports future studies to uncover additional cell-type-specific aging phenotypes or to probe the effects of pharmacologic or physical manipulation of biological systems.

DOI: https://doi.org/10.1101/2025.08.11.669714
Alzheimers Dement. 2025 Aug;21(8): e70550

A brain-derived tau oligomer polymorph is associated with cognitive resilience to Alzheimer's disease.

Michela Marcatti, Batbayar Tumurbaatar, Wen Ru Zhang, Pietro Scaduto, Jutatip Guptarak, Shrinath Kadamangudi, Regan J Schuetze, Anna Fracassi, Rakez Kayed, Giulio Taglialatela.

   INTRODUCTION: Misfolded tau can assemble into oligomers that adopt distinct conformations, referred to as polymorphs, each with unique biochemical and pathological properties. These tau polymorphs are thought to influence disease progression in Alzheimer's disease (AD) and related disorders. Interestingly, some individuals with AD pathology remain cognitively intact (non-demented with Alzheimer's neuropathology [NDAN]), suggesting potential differences in tau polymorph profiles.
METHODS: Brain-derived tau oligomers (BDTOs) were isolated from post mortem hippocampi of AD and NDAN individuals. Their biophysical, biochemical, and functional properties were assessed via protease digestion, immunocharacterization, atomic force microscopy, tau seeding in biosensor cells, hippocampal slice electrophysiology, and SH-SY5Y toxicity assays.
RESULTS: NDAN-BDTOs exhibited protease resistance, different conformational profiles, formed larger aggregates, preserved synaptic function, and reduced neuronal toxicity compared to AD-BDTOs.
DISCUSSION: The data suggests that a structurally stable yet less toxic tau polymorph in NDAN may underlie cognitive resilience, supporting the therapeutic relevance of targeting specific tau polymorphs.
HIGHLIGHTS: Non-demented with Alzheimer's neuropathology (NDAN) brain-derived tau oligomers (BDTOs) exhibit distinct, more stable structural polymorphs compared to those from Alzheimer's disease (AD). NDAN-BDTOs are larger, more protease resistant, and less toxic in cell and hippocampal slice models. Both NDAN- and AD-BDTOs seed tau aggregation, but NDAN-BDTOs promote formation of less toxic assemblies. Structural stability of NDAN-BDTOs may contribute to cognitive resilience despite AD pathology. Mimicking non-toxic tau polymorphs could represent a novel therapeutic strategy for AD.

Keywords:  Alzheimer's disease; brain‐derived tau oligomers; cognitive resilience; non‐demented with Alzheimer's neuropathology; tau polymorphs

DOI:  https://doi.org/10.1002/alz.70550
Neuromolecular Med. 2025 Aug 18. 27(1): 59

A Slower-Progressing TDP-43 rNLS8 Mouse Model for ALS: Implications for Preclinical and Mechanistic Studies.

Cyril Jones Jagaraj, Prachi Mehta, Julie Hunter, Julie D Atkin.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron degeneration, muscle weakness, paralysis, and eventual death, with TAR DNA-binding protein 43 (TDP-43) pathology observed in almost all cases. Mouse models based on TDP-43 are thus essential for studying ALS and developing therapeutic approaches. The TDP-43 rNLS8 mouse model expresses a human TDP-43 transgene with a mutated nuclear localization sequence (hTDP-43 ΔNLS), but this is normally suppressed by the presence of doxycycline (Dox). Disease is initiated by removal of Dox, which replicates key ALS features, including TDP-43 pathology, neuromuscular junction denervation, motor neuron loss, and reduced survival. However, this model has a rapid disease progression which limits its use for extended preclinical studies and investigation of early disease mechanisms. To overcome these limitations, we explored whether maintaining low Dox concentrations in the diet (10-20 mg/kg) could slow disease progression. Our findings demonstrate that this approach significantly reduced hTDP-43 ΔNLS expression (up to 4.8-fold), which delayed disease onset by four weeks. Disease progression, assessed by rotarod performance, grip strength, and neurological scores, was extended from six to 15 weeks, with a threefold increase in survival. Despite slower progression, at the end stage, mice displayed similar levels of neuroinflammation, motor neuron loss, as Dox off mice. These findings highlight slower-progressing TDP-43 rNLS8 mice as a robust model for preclinical and early disease mechanism studies.

Keywords:  ALS; Longer disease course; TDP-43 rNLS8 mice model

DOI:  https://doi.org/10.1007/s12017-025-08871-z
Bioorg Chem. 2025 Aug 10. pii: S0045-2068(25)00746-1. [Epub ahead of print]164 108866

Discovery of oleanolic acid derivatives that inhibit tau protein phosphorylation and neuroinflammation induced by Aβ25-35 in vitro and in vivo.

Zheng Liu, Xing Huang, Miao Zhang, Yin-Sheng Quan, Ya-Lan Wang, Jin-Ying Liu, Wen Zhe Nie, Yu-Qing Zhao, Hong-Yan Guo, Zhe-Shan Quan, Gao Li, Qing-Kun Shen.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder. The primary pathological features of AD are the abnormal deposition of extracellular β-amyloid (Aβ) protein and hyperphosphorylated microtubule-associated protein tau. Excessive Aβ aggregation triggers neuroinflammation. Oleanolic acid (OA) has significant neuroprotective and anti-inflammatory effects. In this study, we designed and synthesized 35 OA derivatives for the treatment of AD, targeting Aβ and hyperphosphorylated tau. The results showed that compound B1, an OA derivative with a tetrazole, had the strongest activity against Aβ25-35-induced cytotoxicity (EC50 = 1.93 ± 0.76 μM), approximately 14.75-fold more potent than OA and could penetrate the BBB. Intracerebroventricular injection of Aβ25-35 to establish an AD-like mouse model, the histopathological results showed that B1 relieved nerve damage, and Morris water maze results showed that B1 improved learning and memory. Mechanistically, B1 reversed the hyperphosphorylation of tau, significantly inhibited the expression of certain immune-related cytotoxic factors, suppressed the MAPK and NF-κB signaling pathways, and significantly inhibited the expression of RAGE and the apoptosis factors Bax/Bcl-2, both in vitro and in vivo. In conclusion, B1 regulates neuroinflammatory mediators in response to Aβ and reverses the hyperphosphorylation of tau, and is a promising multifunctional compound for treating AD.

Keywords:  Alzheimer's disease; Chemical synthesis; Neuroinflammation; Oleanolic acid; Tau protein phosphorylation; Tetrazole derivatives; β-amyloid

DOI:  https://doi.org/10.1016/j.bioorg.2025.108866