bims-proned 2025-01-19 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–01–19
ten papers selected by
Verena Kohler, Umeå University

The α-Synuclein Seeding Amplification Assay for Parkinson's Disease.
Peripheral proteinopathy in neurodegenerative diseases.
Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases.
Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities.
Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation.
Tau destabilization in a familial deletion mutant K280 accelerates its fibrillization and enhances the seeding effect.
Analyzing the potential of neuronal pentraxin 2 as a biomarker in neurological disorders: A literature review.
Alpha-synuclein inhibits the secretion of extracellular vesicles through disruptions in YKT6 lipidation.
Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments.
Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.

Int J Mol Sci. 2025 Jan 04. pii: 389. [Epub ahead of print]26(1):

The α-Synuclein Seeding Amplification Assay for Parkinson's Disease.

Ling-Xiao Yi, Eng King Tan, Zhi Dong Zhou.

  Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Currently, PD is incurable, and the diagnosis of PD mainly relies on clinical manifestations. The central pathological event in PD is the abnormal aggregation and deposition of misfolded α-synuclein (α-Syn) protein aggregates in the Lewy body (LB) in affected brain areas. Behaving as a prion-like seeding, the misfolded α-syn protein can induce and facilitate the aggregation of native unfolded α-Syn protein to aggravate α-Syn protein aggregation, leading to PD progression. Recently, in a blood-based α-Syn seeding amplification assay (SAA), Kluge et al. identified pathological α-Syn seeding activity in PD patients with Parkin (PRKN) gene variants. Additionally, pathological α-syn seeding activity was also identified in sporadic PD and PD patients with Leucine-rich repeat kinase 2 (LRRK2) or glucocerebrosidase (GBA) gene variants. Principally, the α-Syn SAA can be used to detect pathological α-Syn seeding activity, which will significantly enhance PD diagnosis, progression monitoring, prognosis prediction, and anti-PD therapy. The significance and future strategies of α-Syn SAA protocol are highlighted and proposed, whereas challenges and limitations of the assay are discussed.

Keywords:  Parkinson’s disease; biomarker; neurodegeneration; seeding amplification assay; α-synuclein

DOI:  https://doi.org/10.3390/ijms26010389
Transl Neurodegener. 2025 Jan 16. 14(1): 2

Peripheral proteinopathy in neurodegenerative diseases.

Bin Xu, Xia Lei, Ying Yang, Jiayi Yu, Jun Chen, Zhi Xu, Keqiang Ye, Jing Zhang.

  Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.

Keywords:  Amyloid β; Neurodegenerative diseases; Peripheral proteinopathies; TDP-43; Tau; α-Synuclein

DOI:  https://doi.org/10.1186/s40035-024-00461-6
Sci Rep. 2025 Jan 13. 15(1): 1165

Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases.

Fikret Sahin, Aslihan Gunel, Buse Turegun Atasoy, Ulku Guler, Bekir Salih, Isinsu Kuzu, Mehmet Taspinar, Ozgur Cinar, Selda Kahveci.

  NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer's and Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer's and Parkinson's diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling-a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins.

Keywords:  Mental diseases; N-methyl-D-aspartate receptor (NMDAR) antagonists; Neurodegenerative diseases; Proteasome

DOI:  https://doi.org/10.1038/s41598-024-84479-w
Commun Biol. 2025 Jan 15. 8(1): 53

Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities.

Filippa Lo Cascio, Suhyeorn Park, Urmi Sengupta, Nicha Puangmalai, Nemil Bhatt, Nikita Shchankin, Cynthia Jerez, Naomi Moreno, Alice Bittar, Rhea Xavier, Yingxin Zhao, Cankun Wang, Hongjun Fu, Qin Ma, Mauro Montalbano, Rakez Kayed.

Aggregation of microtubule-associated tau protein is a distinct hallmark of several neurodegenerative disorders such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). Tau oligomers are suggested to be the primary neurotoxic species that initiate aggregation and propagate prion-like structures. Furthermore, different diseases are shown to have distinct structural characteristics of aggregated tau, denoted as polymorphs. Here, we investigate the structural and functional differences of amplified brain-derived tau oligomers (aBDTOs) from AD, DLB, and PSP. Our results indicate that the aBDTOs possess different structural and morphological features that impact neuronal function, gene regulation, and ultimately disease progression. The distinct tau oligomeric polymorphs may thus contribute to the development of clinical phenotypes and shape the progression of diseases. Our results can provide insight into developing personalized therapy to target a specific neurotoxic tau polymorph.

DOI: https://doi.org/10.1038/s42003-025-07499-w
Int J Biol Macromol. 2025 Jan 14. pii: S0141-8130(25)00424-6. [Epub ahead of print] 139875

Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation.

Linwei Yu, Xi Li, Tianyi Shi, Ning Li, Donge Zhang, Xikai Liu, Yushuo Xiao, Xinran Liu, Robert B Petersen, Weikang Xue, Yanxun V Yu, De-Sheng Hu, Li Xu, Hong Chen, Ling Zheng, Kun Huang, Anlin Peng.

  Parkinson's disease (PD), a neurodegenerative disorder without cure, is characterized by the pathological aggregation of α-synuclein (α-Syn) in Lewy bodies. Classic deposition pathway and condensation pathway contribute to α-Syn aggregation, and liquid-liquid phase separation is the driving force for condensate formation, which subsequently undergo liquid-solid phase separation to form toxic fibrils. Traditional Chinese Medicine (TCM) has a long history in treating neurodegenerative disease, herein; we identified chemicals from herbs that inhibit α-Syn aggregation. We screened commonly prescribed TCMs for PD from the CNKI database and registered patents, 13 chemicals were identified in the TCMSP databases as candidate inhibitors, among which three phenols, forsythoside B (FTSB), echinacoside (ECH), and 4-hydroxyindole (C4-OH) efficiently inhibit α-Syn aggregation. Moreover, FTSB and ECH increase α-Syn fluidity within condensates, inhibit α-Syn transition into amyloid fibrils and reduce fibril-induced toxicity in SH-SY5Y cells. Importantly, they disaggregated preformed α-Syn amyloid fibrils. Notably, in an α-Syn overexpressing NL5901 C. elegans PD model, either FTSB or ECH treatment significantly extended the lifespan and improved the PD-like movement disorders, both in the preventive and therapeutic treatment approaches, by reducing toxic α-Syn inclusion formation and improving the fluidity of α-Syn. Together, we offer new therapeutic candidates targeting phase separation-associated aggregation for PD.

Keywords:  Inhibitor; Phase separation; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139875
J Biol Chem. 2025 Jan 13. pii: S0021-9258(25)00031-6. [Epub ahead of print] 108184

Tau destabilization in a familial deletion mutant K280 accelerates its fibrillization and enhances the seeding effect.

Gary Jen-Wei Chen, Ming-Yun Chang, Xin-Peng Lin, Debapriya Kundu, Yu-Jen Chang, Yun-Ru Chen.

  Tauopathies cover a range of neurodegenerative diseases in which natively unfolded tau protein aggregates and spreads in the brain during disease progression. To gain insights into the mechanism of tau structure and spreading, here, we examined the biochemical and cellular properties of human full-length wild-type and familial mutant tau, ΔK280, with a deletion at lysine 280. Our results showed that both wild-type and mutant tau are predominantly monomeric by analytical ultracentrifugation. The mutant tau may lose intramolecular contacts and is significantly destabilized assessed by cross-linking mass spectrometry and urea denaturation. Moreover, the mutant tau displayed accelerated fibril formation compared to the wild-type tau. Upon cross-seeding, the wild-type tau was seeded more easily by wild-type seeds than mutant seeds showing that homotypic seeding is more efficient. The wild-type tau was successfully converted to fibrils with mutant signatures by mutant seeds. Live cell cross-correlation fluorescence spectroscopy studies indicated that wild-type tau forms trimeric species and the mutant tau forms a larger assembly and processes higher cell-to-cell transmission. Overall, these findings shed light on the fundamental mechanisms of tau structure/stability, aggregation, and seeding to facilitate future therapeutic development for tauopathies.

Keywords:  Tau; fibrillization; seeding; stability; tauopathy

DOI:  https://doi.org/10.1016/j.jbc.2025.108184
AIMS Neurosci. 2024 ;11(4): 505-519

Analyzing the potential of neuronal pentraxin 2 as a biomarker in neurological disorders: A literature review.

Ubaid Ansari, Jimmy Wen, Burhaan Syed, Dawnica Nadora, Romteen Sedighi, Denise Nadora, Vincent Chen, Forshing Lui.

  Neuronal pentraxin 2 (NP2) plays a significant role in synaptic plasticity, neuronal survival, and excitatory synapse regulation. Emerging research suggests that NP2 is implicated in the pathogenesis of various neurological disorders, including neurodegenerative diseases, neuropsychiatric disorders, and neuropathies. This literature review extensively analyzes NP2's role in these conditions, thereby highlighting its contributions to synaptic dysfunction, neuroinflammation, and neurotoxic protein aggregation. In Alzheimer's and Parkinson's diseases, NP2 is linked to amyloid-beta aggregation and dopaminergic neuron degeneration, respectively. Additionally, altered NP2 expression is observed in schizophrenia and bipolar disorder, thus suggesting its involvement in synaptic dysfunction and neurotransmitter imbalance. In neuropathic pain and epilepsy, NP2 modulates the synaptic plasticity and inflammatory responses, with altered levels correlating with disease severity. Furthermore, NP2's involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) emphasizes its broad impact on neuronal health. Understanding NP2's multifaceted roles may reveal novel therapeutic targets and improve the clinical outcomes for these neurological disorders. Though the precise role of NP2 remains uncertain, its clinical potential and initial findings justify further investigations into neuronal pentraxins and other related neuroproteins.

Keywords:  Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; epilepsy; neuronal pentraxin 2; neuropathic pain; schizophrenia; synaptic plasticity

DOI:  https://doi.org/10.3934/Neuroscience.2024031
J Neurosci. 2025 Jan 10. pii: e2350232024. [Epub ahead of print]

Alpha-synuclein inhibits the secretion of extracellular vesicles through disruptions in YKT6 lipidation.

Taiji Tsunemi, Yuta Ishiguro, Asako Yoroisaka, Dou Feng, Tomoyo Shimada, Shunichi Niiyama, Yukiko Sasazawa, Keiichi Ishikawa, Wado Akamatsu, Nobutaka Hattori.

Parkinson's disease is characterized by the presence of α-synuclein (α-syn) primarily containing Lewy bodies in neurons. Despite decades of extensive research on α-syn accumulation, its molecular mechanisms have remained largely unexplored. Recent studies by us and others have suggested that extracellular vesicles (EVs), especially exosomes, can mediate the release of α-syn from cells, and inhibiting this pathway could result in increased intracellular α-syn levels. In this study, we have discovered that elevated levels of α-syn themselves lead to reduced α-syn -containing EVs in α-syn inducible H4 cells and induced pluripotent stem cell-derived dopaminergic (DA) neurons from both sexes. Our investigations have revealed that the impairment in EV secretion is not due to their generation but rather a consequence of changes in a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, YKT6. Specifically, as α-syn levels increase, membrane-associated YKT6 is reduced. Pharmacological inhibition of farnesylation using FTI has led to decreased EV secretion and subsequent elevated levels of α-syn. In summary, our findings suggest that increased levels of α-syn impair YKT6-mediated EV secretion, establishing a detrimental cycle of intracellular α-syn accumulation in human DA neurons.Significance Statement Neurodegenerative disorders, including Parkinson's disease (PD), are characterized by the pathological accumulation of insoluble proteins, primarily in neurons. Regulating intracellular levels of these proteins is critical. Despite extensive research for decades, the precise mechanism of these protein deposits remains unexplained. In this study, we discovered that extracellular vesicles (EVs) play a pivotal role in regulating alpha-synuclein (a-syn) levels through release from neurons. Furthermore, increased levels of a-syn impede its EV secretion, creating a pathological loop. Elevated levels of a-syn interfere with the localization of YKT6, a SNARE protein, to the vesicle membrane by inhibiting YKT6 palmitoylation. These findings illustrate a novel mechanism of a-syn accumulation in neurons and provide a target to potentially mitigate PD pathology.

DOI: https://doi.org/10.1523/JNEUROSCI.2350-23.2024
Sci Adv. 2025 Jan 17. 11(3): eadr7008

Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments.

Maria Milanesi, Z Faidon Brotzakis, Michele Vendruscolo.

Several human disorders, including Alzheimer's disease (AD), are characterized by the aberrant formation of amyloid fibrils. In many cases, the amyloid core is flanked by disordered regions, known as fuzzy coat. The structural properties of fuzzy coats, and their interactions with their environments, however, have not been fully described to date. Here, we generate conformational ensembles of two brain-derived amyloid filaments of Aβ42, corresponding respectively to the familial and sporadic forms of AD. Our approach, called metadynamic electron microscopy metainference (MEMMI), provides a characterization of the transient interactions between the fuzzy coat and the cross-β core of the filaments. These calculations indicate that the familial AD filaments are less soluble than the sporadic AD filaments, and that the fuzzy coat contributes to solubilizing both types of filament. These results illustrate how the metainference approach can help analyze cryo-EM maps for the characterization of the properties of amyloid fibrils.

DOI: https://doi.org/10.1126/sciadv.adr7008
Mol Ther. 2025 Jan 10. pii: S1525-0016(25)00008-5. [Epub ahead of print]

Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.

Vicente Valenzuela, Daniela Becerra, José I Astorga, Matías Fuentealba, Guillermo Diaz, Leslie Bargsted, Carlos Chacón, Alexis Martinez, Romina Gozalvo, Kasey Jackson, Vania Morales, Macarena Las Heras, Giovanni Tamburini, Leonard Petrucelli, Pablo Sardi, Lars Plate, Claudio Hetz.

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAV) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended life span of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.

DOI: https://doi.org/10.1016/j.ymthe.2025.01.004