bims-proned 2025-03-16 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–03–16
ten papers selected by
Verena Kohler, Umeå University

Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.
Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.
Molecular insight into cross-interaction between amyloid β isoforms and its effect on aggregation pathways.
Neuroprotective efficacy of berberine and caffeine against rotenone-induced neuroinflammatory and oxidative disturbances associated with Parkinson's disease via inhibiting α-synuclein aggregation and boosting dopamine release.
Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies.
Distinct neuronal vulnerability and metabolic dysfunctions are characteristic features of fast-progressing Alzheimer's patients with Lewy bodies.
The interrelationship between intestinal immune cells and enteric α-synuclein in the progression of Parkinson's disease.
Membrane-assisted Aβ40 aggregation pathways.
Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.
HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).

Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2402117122

Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.

Elizabeth A Johnson, Raghad Nowar, Kirsten L Viola, Weijian Huang, Sihang Zhou, Maíra A Bicca, Wei Zhu, Daniel L Kranz, William L Klein, Richard B Silverman.

  Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (AβOs), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. AβO buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L- and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against AβO buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.

Keywords:  Alzheimer’s disease; amyloid-beta oligomers; neurodegenerative disease; protein aggregation

DOI:  https://doi.org/10.1073/pnas.2402117122
bioRxiv. 2025 Mar 02. pii: 2025.02.27.640500. [Epub ahead of print]

Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.

Lathan Lucas, Phoebe S Tsoi, My Diem Quan, Kyoung-Jae Choi, Josephine C Ferreon, Allan Chris M Ferreon.

Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation 1-3 . Tau and α- synuclein (αSyn) are neuronal proteins that form heterotypic (Tau:αSyn) condensates associated with both physiological and pathological processes. Tau and αSyn functionally regulate microtubules 8-12 , but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases 4,5,6,7 , which highlights the paradoxically ambivalent effect of Tau:αSyn condensation in health and disease. Here, we show that tubulin modulates Tau:αSyn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:αSyn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:αSyn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and αSyn oligomerization and aggregation. We distinguished distinct Tau and αSyn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimer's disease and Parkinsons disease patients 13,14 , results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:αSyn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/αSyn mixed pathologies.

DOI: https://doi.org/10.1101/2025.02.27.640500
J Biomol Struct Dyn. 2025 Mar 07. 1-11

Molecular insight into cross-interaction between amyloid β isoforms and its effect on aggregation pathways.

Li Wang, Sanghwan Park, Jae Hong Choi, Chang Young Lee, Kilho Eom, Taeyun Kwon.

  The self-aggregation of amyloid β (Aβ) proteins has played a crucial role in the pathogenesis of Alzheimer's diseases. Despite previous studies on the aggregation process of Aβ proteins, little is known about how the cross-interaction between Aβ isoforms affects the aggregation pathways and the resulting structures of Aβ aggregates. Here, we study the cross-interaction between Aβ40 and Aβ42 during their aggregation process by measuring the aggregation kinetics and the structures of Aβ aggregates under varied concentrations of Aβ isoform proteins in their mixture. We found that the mixture of Aβ40 and Aβ42 monomers results in the concentration-dependent aggregation process leading to different aggregate structures in such a way that the different concentrations of Aβ40 and Aβ42 induce the different structural types of aggregates such as different sized oligomers or fibrils with their different morphologies and flexibilities. Moreover, we investigate the effect of Aβ40 (or Aβ42) oligomer and fibril seeds in the aggregation pathway of Aβ42 (or Aβ40). We show that the oligomer (or fibril) seed affects not only the aggregation kinetics but also the structures of Aβ aggregates. Our study sheds light on the cross-interaction between Aβ isoforms at primary nucleation level and its role in the aggregation pathways.

Keywords:  Aβ isoform; Cross-interaction; aggregation; fibril seed; oligomer seed

DOI:  https://doi.org/10.1080/07391102.2025.2475221
Inflammopharmacology. 2025 Mar 09.

Neuroprotective efficacy of berberine and caffeine against rotenone-induced neuroinflammatory and oxidative disturbances associated with Parkinson's disease via inhibiting α-synuclein aggregation and boosting dopamine release.

Tasnim S Waheeb, Mohammad A Abdulkader, Doaa A Ghareeb, Mohamed E Moustafa.

  Parkinson's disease (PD) is characterized by motor impairment, glial-mediated inflammation, redox imbalance, and α-synuclein (α-syn) aggregation. Conventional therapies relieve early PD symptoms, but they do not repair dopaminergic neurons. Berberine (BBR) and caffeine (CAF), both natural alkaloids, exhibited neuroprotective effects in many neurodegenerative disorders. Consequently, we hypothesized that the combination of BBR and CAF therapies would offer protection against PD-related impairments in the rotenone (ROT)-induced rat model when compared to the commercial drug, metformin (MTF). Our results showed that the combined administration of BBR (25 mg/kg/day) and CAF (2.5 mg/kg/day) for four weeks prevented motor deficits, weight reduction, dopamine (DA) depletion, and monoamine oxidase (MAO) activity in ROT-induced rats in comparison with monotherapy of BBR and CAF along with MTF. This combination produced a notable neuroprotective effect by reducing tumor necrosis factor (TNF)-α and interleukin-16 (IL-6) in midbrain of rats. BBR and CAF combinations markedly normalized tyrosine hydroxylase (TH) levels and decreased total α-syn and α-syn-pser129 aggregation and increased protein phosphatase 2A (PP2A) levels. Histological analysis indicated that damaged neurons exhibited significant amelioration with the co-administration of BBR and CAF. The molecular docking results indicated that both BBR and CAF had notable binding affinity for the protein pocket surrounding the α-syn, PP2A, and TH in comparison to MTF. They are predicted to serve as effective inhibitors of enzyme-mediated phosphorylation of α-syn-pser129. Conclusively, combined BBR and CAF administration presents a novel strategy for neuroprotection by blocking the initial events in PD incidence, demonstrating considerable anti-oxidative and anti-inflammatory benefits relative to MTF.

Keywords:  Molecular docking; Motor impairment; Natural combination therapy; Neurodegenerative diseases; Protein phosphatase 2A; Rotenone model; Tyrosine hydroxylase

DOI:  https://doi.org/10.1007/s10787-025-01661-w
Cell Mol Neurobiol. 2025 Mar 13. 45(1): 24

Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies.

André Nadais, Inês Martins, Ana Gabriela Henriques, Diogo Trigo, Odete A B da Cruz E Silva.

  Protein aggregation is remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first is characterized by hyperphosphorylated tau protein and Aβ peptide deposition, thus forming intracellular neurofibrillary tangles and extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates and deposits as Lewy bodies. Considerable research has focused on developing protein aggregation models to be explored as research tools. In the present work, four in vitro models for studying protein aggregation were studied and compared, namely treatment with: the toxic Aβ1-42 peptide, the isoflavone rotenone, the ATP synthase inhibitor oligomycin, and the proteosome inhibitor MG-132. All treatments result in aggregation-relevant events in the human neural SH-SY5Y cell line, but significant model-dependent differences were observed. In terms of promoting aggregate formation, Aβ and MG-132 provoked the greatest effect, but only MG-132 was associated with an increase in HSP-70 chaperone expression. In fact, the type of aggregates formed appear to be dependent on the treatment employed, and supports the hypothesis that Aβ exposure is a relevant AD model, and rotenone is a valid model for PD. Furthermore, the results revealed that protein phosphorylation is relevant to aggregate formation and as expected, tau co-localized to the deposits formed in the Aβ peptide aggregate induction cell model. In summary, different molecular processes, from overall and specific protein aggregation to proteostatic modulation, can be induced by using distinct aggregation modelling strategies, and these can be used to study different protein-aggregation-related processes associated with distinct neuropathologies.

Keywords:  Alzheimer´s disease; Aβ1-42 peptide; Mitochondrial dysfunction; Parkinson´s disease; Protein aggregation

DOI:  https://doi.org/10.1007/s10571-025-01539-z
J Biol Chem. 2025 Mar 10. pii: S0021-9258(25)00245-5. [Epub ahead of print] 108396

Distinct neuronal vulnerability and metabolic dysfunctions are characteristic features of fast-progressing Alzheimer's patients with Lewy bodies.

Mohammed Waseequr Rahman, Preeti Sharma, Trisha Chattopadhyay, Sivaprakasam R Saroja.

Tau protein accumulation is linked to dementia progression in Alzheimer's disease (AD), with potential co-pathologies contributing to it. The progression of dementia in AD patients varies between individuals, and the association between co-pathology and heterogeneity in dementia progression rate remains unclear. We used longitudinal cohort data, postmortem brain tissues, and biochemical methods such as immunoassays and proteomic profiling to investigate the molecular components associated with progression rate. We report that AD with comorbidities, such as dementia with Lewy bodies (DLB) and TDP-43 pathology, progress faster than AD alone. AD-DLB patients had higher levels of soluble oligomeric tau proteins and lower levels of insoluble tau proteins compared to those with AD alone. Our data suggest that α-synuclein fibrils may enhance tau aggregation through cross-seeding. The prefrontal cortex is more vulnerable to Lewy body pathology than the temporal cortex, and Tau and α-synuclein aggregate in distinct neuronal populations, indicating selective neuronal and regional vulnerability to their respective pathologies. Dysfunctional metabolic pathways were more strongly associated with fast-progressing AD-DLB patients. Our study suggests that comorbidities, such as α-synuclein aggregation and metabolic dysfunctions, are associated with rapidly progressing AD patients, highlighting the importance of patient subgrouping for clinical trials.

DOI: https://doi.org/10.1016/j.jbc.2025.108396
Neurol Sci. 2025 Mar 14.

The interrelationship between intestinal immune cells and enteric α-synuclein in the progression of Parkinson's disease.

Yuan-Kai Cheng, Hao-Sen Chiang.

  Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairment, resulting from the accumulation of α-synuclein and neuronal cell death in the substantia nigra of the midbrain. Emerging evidence suggests that α-synuclein aggregation may originate in the enteric nervous system (ENS) and subsequently propagate to the brain via the vagus nerve. Clinical observations, such as prodromal gastrointestinal dysfunction in PD patients and the increased incidence of PD among individuals with inflammatory bowel disease, support the hypothesis that abnormal intestinal inflammation may contribute to the onset of motor dysfunction and neuropathology in PD. This review examines recent findings on the interplay between intestinal immune cells and α-synuclein aggregation within the framework of gut-originated PD pathogenesis. It begins by discussing evidence linking dysbiosis and intestinal inflammation to α-synuclein aggregation in the ENS. Additionally, it explores the potential role of intestinal immune cells in influencing enteric neurons and α-synuclein aggregation, furthering the understanding of PD development.

Keywords:  Alpha-synuclein; Dysbiosis; Enteric nervous system; Inflammatory bowel diseases; Intestinal immune cells; Intestinal inflammation; Parkinson’s disease

DOI:  https://doi.org/10.1007/s10072-025-08114-w
Cell Rep Phys Sci. 2025 Feb 19. pii: 102436. [Epub ahead of print]6(2):

Membrane-assisted Aβ40 aggregation pathways.

Fidha Nazreen Kunnath Muhammedkutty, Huan-Xiang Zhou.

Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here, we used extensive molecular dynamics (MD) simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β sheet (residues Q15-D23) and a bent β sheet (residues A30-V36). This work presents a comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.

DOI: https://doi.org/10.1016/j.xcrp.2025.102436
Biochem Biophys Res Commun. 2025 Mar 03. pii: S0006-291X(25)00296-7. [Epub ahead of print]756 151582

Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.

Aisheng Zhan, Keke Zhong, Kejing Zhang.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.

DOI: https://doi.org/10.1016/j.bbrc.2025.151582
Biochem Biophys Res Commun. 2025 Feb 28. pii: S0006-291X(25)00247-5. [Epub ahead of print]756 151533

HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).

Battur Tserennadmid, Min-Kyung Nam, Ju-Hwang Park, Hyangshuk Rhim, Seongman Kang.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) protein aggregates in motor neurons, leading to progressive motor dysfunction and ultimately death. While the molecular chaperone heat shock protein 104 (Hsp104) has been shown to reduce protein misfolding by disaggregating protein aggregates, fully degrading these disaggregated proteins remains a significant challenge. In this study, we have investigated the effects of Hsp104 and its hyperactive variant, HAP, in combination with caseinolytic protease P (CIpP), on the disaggregation and degradation of SOD1 aggregates. Using laser confocal microscopy, fluorescence loss in photobleaching (FLIP), and biomolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assays, we demonstrate that Hsp104 effectively disaggregates SOD1 aggregates across 14 different G93 mutants, classified based on the properties of substituted amino acids, thus restoring protein mobility. Notably, the HAP/CIpP system not only disaggregates ALS-associated SOD1G93A aggregates but also promotes their proteolytic degradation, as evidenced by a significant reduction in high-order oligomers observed through BiFC and FRET assays. This dual mechanism of action presents. the HAP/CIpP system holds significant therapeutic potential for ALS and other neurodegenerative diseases characterized by protein aggregates, as it enables both effective disaggregation and degradation of toxic protein aggregates, thereby maintaining protein homeostasis.

Keywords:  HAP/CIpP complex; Hsp104; Protein disaggregation-degradation; SOD1 aggregates

DOI:  https://doi.org/10.1016/j.bbrc.2025.151533