bims-proned 2025-01-26 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–01–26
thirteen papers selected by
Verena Kohler, Umeå University

Lipid-induced condensate formation from the Alzheimer's Aβ peptide triggers amyloid aggregation.
Ergothioneine exerts neuroprotective effects in Parkinson's disease: Targeting α-synuclein aggregation and oxidative stress.
Neurological Diseases can be Regulated by Phase Separation.
MitoStores: stress-induced aggregation of mitochondrial proteins.
How close is autophagy-targeting therapy for Alzheimer's disease to clinical use? A summary of autophagy modulators in clinical studies.
Histone deacetylase's regulates Tau function in Alzheimer's disease.
Charge Modification of Lysine Mitigates Amyloid-β Aggregation.
Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein.
The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes.
α-Synuclein deposition in the kidney may contribute to Parkinson's disease.
Lipidic folding pathway of α-Synuclein via a toxic oligomer.
E46K α-Synuclein Mutation Fails to Promote Neurite Outgrowth by Not Inducing Cdc42EP2 Expression, Unlike Wild-Type or A53T α-Synuclein in SK-N-SH Cells.
Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.

Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2401307122

Lipid-induced condensate formation from the Alzheimer's Aβ peptide triggers amyloid aggregation.

Greta Šneiderienė, Alicia González Díaz, Sourav Das Adhikari, Jiapeng Wei, Thomas Michaels, Tomas Šneideris, Sara Linse, Michele Vendruscolo, Kanchan Garai, Tuomas P J Knowles.

  The onset and development of Alzheimer's disease is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies at later stages of the disease, but the fundamental molecular steps in early stage disease that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain unknown. Here, we show that the Aβ peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells. Our results reveal that these Aβ condensates can significantly accelerate the primary nucleation step in the amyloid conversion cascade that leads to the formation of amyloid aggregates. We show that Aβ condensates contain phospholipids, are intrinsically heterogeneous, and are prone to undergo a liquid-to-solid transition leading to the formation of amyloid fibrils. These findings uncover the liquid-liquid phase separation behavior of the Aβ peptide and reveal a molecular step very early in the amyloid-β aggregation process.

Keywords:  amyloid aggregation; amyloid β; biomolecular condensation; liquid–liquid phase separation

DOI:  https://doi.org/10.1073/pnas.2401307122
Food Res Int. 2025 Feb;pii: S0963-9969(24)01661-2. [Epub ahead of print]201 115590

Ergothioneine exerts neuroprotective effects in Parkinson's disease: Targeting α-synuclein aggregation and oxidative stress.

Wen Gao, Yang Wang, Fuhao Wang, Xinni Wu, Fuping Lu, Fufeng Liu.

  Ergothioneine (EGT) is a natural dietary antioxidant derived from certain edible mushrooms, commonly used as a food additive and supplement, but its effects on Parkinson's Disease (PD) are still unclear. The accumulation of α-synuclein (α-syn) plays a pivotal role in the pathogenesis and development of PD. Here, this study demonstrated that EGT effectively inhibits α-syn aggregation, disrupts mature fibers, and reduces associated cytotoxicity and oxidative stress. The beneficial effects of EGT were confirmed in Caenorhabditis elegans, where it protected dopaminergic neurons, prolonged lifespan and enhanced behavioral functions by reducing α-syn plaque accumulation and associated oxidative stress. Molecular dynamics simulation revealed that EGT interacts directly with α-syn pentamer through van der Waals and electrostatic forces, disrupting the structural stability of the preformed pentamer. Furthermore, animal studies validated that EGT alleviated neuronal damage and improved behavioral deficits by reducing α-syn aggregation, oxidative stress and inflammatory response. In conclusion, EGT presents promising potential as a dietary supplement for preventing and alleviating PD.

Keywords:  Ergothioneine; Food supplement; Oxidative stress; Parkinson’s disease; α-synuclein

DOI:  https://doi.org/10.1016/j.foodres.2024.115590
Rev Physiol Biochem Pharmacol. 2025 ;187 273-338

Neurological Diseases can be Regulated by Phase Separation.

Colin D McCaig.

  Several neurological diseases arise from abnormal protein aggregation within neurones and this is closely regulated by phase separation. One such is motor neurone disease and aberrant aggregation of superoxide dismutase. Again these events are regulated by electrical forces that are examined.

Keywords:  ALS; LLPS; Liquid–liquid phase separation; Neurological disease; Phase separation; Protein aggregation; Protein misfolding; SOD1; π–π stacking interactions

DOI:  https://doi.org/10.1007/978-3-031-68827-0_16
Biol Chem. 2025 Jan 21.

MitoStores: stress-induced aggregation of mitochondrial proteins.

Pragya Kaushik, Johannes M Herrmann, Katja G Hansen.

  Most mitochondrial proteins are synthesized in the cytosol and post-translationally imported into mitochondria. If the rate of protein synthesis exceeds the capacity of the mitochondrial import machinery, precursor proteins can transiently accumulate in the cytosol. The cytosolic accumulation of mitochondrial precursors jeopardizes cellular protein homeostasis (proteostasis) and can be the cause of diseases. In order to prevent these toxic effects, most non-imported precursors are rapidly degraded by the ubiquitin-proteasome system. However, cells employ a second layer of defense which is the facilitated sequestration of mitochondrial precursor proteins in transient protein aggregates. The formation of such structures is triggered by nucleation factors such as small heat shock proteins. Disaggregases and chaperones can liberate precursors from cytosolic aggregates to pass them on to the mitochondrial import machinery or, under persistent stress conditions, to the proteasome for degradation. Owing to their role as transient buffering systems, these aggregates were referred to as MitoStores. This review articles provides a general overview about the MitoStore concept and the early stages in mitochondrial protein biogenesis in yeast and, in cases where aspects differ, in mammalian cells.

Keywords:  aggregates; mitochondria; mitostores; proteasome; protein targeting; quality control

DOI:  https://doi.org/10.1515/hsz-2024-0148
Front Cell Dev Biol. 2024 ;12 1520949

How close is autophagy-targeting therapy for Alzheimer's disease to clinical use? A summary of autophagy modulators in clinical studies.

Sofia Miranda Fernandes, Johanna Mayer, Per Nilsson, Makoto Shimozawa.

  Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by progressive decline of memory and cognitive functions, and it is the leading cause of dementia accounting for 60%-80% of dementia patients. A pathological hallmark of AD is the accumulation of aberrant protein/peptide aggregates such as extracellular amyloid plaques containing amyloid-beta peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. These aggregates result from the failure of the proteostasis network, which encompasses protein synthesis, folding, and degradation processes. Autophagy is an intracellular self-digesting system responsible for the degradation of protein aggregates and damaged organelles. Impaired autophagy is observed in most neurodegenerative disorders, indicating the link between autophagy dysfunction and these diseases. A massive accumulation of autophagic vacuoles in neurons in Alzheimer's brains evidences autophagy impairment in AD. Modulating autophagy has been proposed as a therapeutic strategy for AD because of its potential to clear aggregated proteins. However, autophagy modulation therapy for AD is not yet clinically available. This mini-review aims to summarize clinical studies testing potential autophagy modulators for AD and to evaluate their proximity to clinical use. We accessed clinicaltrials.gov provided by the United States National Institutes of Health to identify completed and ongoing clinical trials. Additionally, we discuss the limitations and challenges of these therapies.

Keywords:  Alzheimer’s disease; autophagy impairment; autophagy modulators; clinical studies; protein homeostasis

DOI:  https://doi.org/10.3389/fcell.2024.1520949
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00094-4. [Epub ahead of print]143 339-361

Histone deacetylase's regulates Tau function in Alzheimer's disease.

Subashchandrabose Chinnathambi.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disease associated with dementia and neuronal impairments in brain. AD is characterized histopathologically by two hallmark lesions: abnormally phosphorylated Tau inside neurons as intracellular NFTs and extracellular accumulation of amyloid β peptide (Aβ). Furthermore, it is unable to clarify the distinction between the brief association between the development and build-up of Aβ and the commencement of illness. Additionally, a number of experimental findings suggest that symptoms related to Aβ may only manifest within the framework of anabatic Tauopathies. Tau, a natively unfolded protein, essentially involved in microtubule binding and assembly. Tau protein consists of truncated segment and the purpose of this truncated fragment is to initiate and promote the conversion of soluble Tau into aggregates. The most common aberrant posttranslational change found in Neuro Fibrillary Tangles is hyperphosphorylation, which is essentially composed of aggregated Tau. Tau phosphorylation and acetylation of Tau protein at the locations controlled by histone deacetylase 6 compete, which modulates Tau function. Considering the potential benefits of targeting HDAC6 in AD, we propose focusing on the role of HDAC6 in regulating Tau functions and the other targets are the therapeutic understanding of AD.

Keywords:  Alzheimers disease; Cytoskeletal regulations; Histone deacetylase; Tau interaction; Tau phosphorylation

DOI:  https://doi.org/10.1016/bs.apcsb.2024.09.008
Chembiochem. 2025 Jan 21. e202400906

Charge Modification of Lysine Mitigates Amyloid-β Aggregation.

HaeMin Kwon, JiMin Kim, InWook Park, Suhyun Ye, MinSeol Park, Seung-Hoon Yang, Hye Yun Kim, YoungSoo Kim.

  Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides, which aggregate into toxic structures such as oligomers, fibrils, and plaques. The presence of these Aβ aggregates in the brain plays a crucial role in the pathophysiology, leading to synaptic dysfunction and cognitive impairment. Understanding how physiological factors affect Aβ aggregation is essential, and therefore, exploring their influence in vitro will likely provide insights into their role in AD pathology. In this study, we investigated the effects of physiological, free amino acids on Aβ aggregation dynamics. We focused on positively charged amino acids, particularly lysine, and employed a chemical modification, methylation, to neutralize its charge. Our analyses revealed that modified lysine significantly reduced Aβ aggregation, indicating that charge distribution of amino acids plays a crucial role in modulating Aβ aggregation behavior. These findings enhance our understanding of the regulatory factors influencing Aβ aggregation and highlight important considerations for future research on Aβ.

Keywords:  Aggregation inhibitors; Alzheimer's disease; Amino acid; Amyloid-β; Charge distribution

DOI:  https://doi.org/10.1002/cbic.202400906
bioRxiv. 2025 Jan 08. pii: 2025.01.07.631748. [Epub ahead of print]

Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein.

Yarra Venkatesh, Karthik B Narayan, Tobias Baumgart, E James Petersson.

Molecular rotor-based fluorophores (RBFs) that are target-selective and sensitive to both polarity and viscosity are valuable for diverse biological applications. Here, we have designed next-generation RBFs based on the underexplored bimane fluorophore through either changing in aryl substitution or varying π-linkages between the rotatable electron donors and acceptors to produce red-shifted fluorescence emissions with large Stokes shifts. RBFs exhibit a twisted intramolecular charge transfer mechanism that enables control of polarity and viscosity sensitivity, as well as target selectivity. These features enable their application in: (1) turn-on fluorescent detection of α-synuclein (αS) fibrils, a hallmark of Parkinson's disease (PD), including amplified fibrils from patient samples; (2) monitoring early misfolding and oligomer formation during αS aggregation; and (3) selective imaging of αS condensates formed by liquid-liquid phase separation (LLPS). In all three cases, we show that our probes have high levels of selectivity for αS versus other aggregating proteins. These properties enable one to study the interplay of αS and tau in amyloid aggregation and the mechanisms underlying neurodegenerative disorders.

DOI: https://doi.org/10.1101/2025.01.07.631748
Sci Adv. 2025 Jan 24. 11(4): eado3852

The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes.

Yvonne Eibach, Silke Kreher, Mareike S Poetsch, Ay Lin Kho, Ulrich Gaertner, Christoph S Clemen, Rolf Schröder, Kai Guo, Hendrik Milting, Benjamin Meder, Michael Potente, Manfred Richter, Andre Schneider, Silke Meiners, Mathias Gaute, Thomas Braun.

Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of mUsp5 leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs.

DOI: https://doi.org/10.1126/sciadv.ado3852
Nat Neurosci. 2025 Jan 23.

α-Synuclein deposition in the kidney may contribute to Parkinson's disease.

DOI: https://doi.org/10.1038/s41593-024-01867-1
Nat Commun. 2025 Jan 17. 16(1): 760

Lipidic folding pathway of α-Synuclein via a toxic oligomer.

Vrinda Sant, Dirk Matthes, Hisham Mazal, Leif Antonschmidt, Franz Wieser, Kumar T Movellan, Kai Xue, Evgeny Nimerovsky, Marianna Stampolaki, Magdeline Nathan, Dietmar Riedel, Stefan Becker, Vahid Sandoghdar, Bert L de Groot, Christian Griesinger, Loren B Andreas.

Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently determined by single-particle cryo-electron microscopy. By contrast, smaller pre-fibrillar α-Synuclein (αS) oligomers, crucial for initiating amyloidogenesis, remain largely uncharacterized. We report an atomic-resolution structural characterization of a toxic pre-fibrillar aggregation intermediate (I1) on pathway to the formation of lipidic fibrils, which incorporate lipid molecules on protofilament surfaces during fibril growth on membranes. Super-resolution microscopy reveals a tetrameric state, providing insights into the early oligomeric assembly. Time resolved nuclear magnetic resonance (NMR) measurements uncover a structural reorganization essential for the transition of I1 to mature lipidic L2 fibrils. The reorganization involves the transformation of anti-parallel β-strands during the pre-fibrillar I1 state into a β-arc characteristic of amyloid fibrils. This structural reconfiguration occurs in a conserved structural kernel shared by a vast number of αS-fibril polymorphs including extracted fibrils from Parkinson's and Lewy Body Dementia patients. Consistent with reports of anti-parallel β-strands being a defining feature of toxic αS pre-fibrillar intermediates, I1 impacts viability of neuroblasts and disrupts cell membranes, resulting in an increased calcium influx. Our results integrate the occurrence of anti-parallel β-strands as salient features of toxic oligomers with their significant role in the amyloid fibril assembly pathway. These structural insights have implications for the development of therapies and biomarkers.

DOI: https://doi.org/10.1038/s41467-025-55849-3
Brain Sci. 2024 Dec 25. pii: 9. [Epub ahead of print]15(1):

E46K α-Synuclein Mutation Fails to Promote Neurite Outgrowth by Not Inducing Cdc42EP2 Expression, Unlike Wild-Type or A53T α-Synuclein in SK-N-SH Cells.

Hyunja Jung, Seonghan Kim.

   BACKGROUND/OBJECTIVES: α-Synuclein (α-syn) protein is a major pathological agent of familial Parkinson's disease (PD), and its levels and aggregations determine neurotoxicity in PD pathogenesis. Although the pathophysiological functions of α-syn have been extensively studied, its biological functions remain elusive, and there are reports of wild-type (WT) α-syn and two missense mutations of α-syn (A30P and A53T) inducing protective neuritogenesis through neurite outgrowth. However, the function of another α-syn mutation, E46K, has not been fully elucidated. Thus, we compared the effect of E46K α-syn with other types to identify the mechanisms underlying neurite outgrowth.
METHODS: We transfected SK-N-SH cells with WT and mutant (A53T and E46K) α-syn to investigate the effects of their overexpression on neurite outgrowth. Then, we compared the differential effects of α-syn on neurite outgrowth using microscopic analysis, including confocal microscopy. We also analyzed the differential regulation of cell division control 42 effector protein 2 (Cdc42EP2) using real-time quantitative polymerase chain reaction and western blot analysis. Finally, to confirm the implication of neurite outgrowth, we knocked down Cdc42EP2 using small interfering RNA.
RESULTS: Unlike WT and A53T α-syn, E46K α-syn failed to promote neurite outgrowth by not inducing Cdc42EP2 and subsequent βIII-tubulin expression. Cdc42EP2 knockdown impaired neurite outgrowth in WT and A53T α-syn transfectants.
CONCLUSIONS: Our findings suggest that WT and mutant α-syn are linked to Cdc42EP2 production in neuritogenesis, implying α-syn involvement in the physiological function of axon growth and synapse formation. Thus, α-syn may be a potential therapeutic target for PD.

Keywords:  Cdc42EP2; E46K mutation; Parkinson’s disease; neurite outgrowth; α-synuclein

DOI:  https://doi.org/10.3390/brainsci15010009
Mol Neurodegener. 2025 Jan 23. 20(1): 10

Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.

Grace Kuo, Ramhari Kumbhar, William Blair, Valina L Dawson, Ted M Dawson, Xiaobo Mao.

  α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer's disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies.

Keywords:  Prion-like; Receptor; Spreading; Therapeutic targets; α-synuclein

DOI:  https://doi.org/10.1186/s13024-025-00797-1