α-synuclein and tau: interactions, cross-seeding, and the redefinition of synucleinopathies as complex proteinopathies

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: March 27, 2025

Neurodegenerative diseases are characterized by protein aggregation and overlapping pathologies, challenging traditional classifications highlighting shared underlying mechanisms. Parkinson’s disease related synucleinopathies, including Lewy body dementia multiple system atrophy, highlight the interplay between α-synuclein tau, two key proteins implicated in these disorders. Recent studies reveal that tau co-aggregate, interact synergistically, propagate via prion-like mechanisms, exacerbating neuronal dysfunction. This review examines physiological roles pathological transitions of α-synuclein, emphasizing their microtubule dynamics, synaptic regulation, structural heterogeneity aggregates. Evidence from post-mortem brains, transgenic models, proteomic analyses underscores significance soluble oligomers as primary neurotoxic species explores diverse molecular composition bodies glial cytoplasmic inclusions. The co-localization influenced genetic factors post-translational modifications, offers insights into mechanisms across synucleinopathies tauopathies. These findings advocate for integrated therapeutic strategies targeting cross-seeding proteostatic disruption while preserving roles. By framing neurodegeneration a collapse networks rather than isolated proteinopathies, this work proposes paradigm shift toward understanding treating complex neurodegenerative

Language: Английский

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Advancing Alzheimer's Therapy: Computational Strategies and Treatment Innovations

IBRO Neuroscience Reports, Journal Year: 2025, Volume and Issue: 18, P. 270 - 282

Published: Feb. 4, 2025

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition distinguished by the occurrence of memory impairment, cognitive deterioration, and neuronal impairment. Despite extensive research efforts, conventional treatment strategies primarily focus on symptom management, highlighting need for innovative therapeutic approaches. This review explores challenges AD integration computational methodologies to advance interventions. A comprehensive analysis recent literature was conducted elucidate broad scope etiology limitations drug discovery Our findings underscore critical role models in elucidating mechanisms, identifying targets, expediting discovery. Through simulations, researchers can predict efficacy, optimize lead compounds, facilitate personalized medicine Moreover, machine learning algorithms enhance early diagnosis enable precision analyzing multi-modal datasets. Case studies highlight application techniques therapeutics, including suppression crucial proteins implicated progression repurposing existing drugs management. Computational interplay between oxidative stress neurodegeneration, offering insights into potential Collaborative efforts biologists, pharmacologists, clinicians are essential translate clinically actionable interventions, ultimately improving patient outcomes addressing unmet medical needs individuals affected AD. Overall, integrating represents promising paradigm shift solutions overcome transform landscape treatment.

Language: Английский

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Meroterpenoids from Terrestrial and Marine Fungi: Promising Agents for Neurodegenerative Disorders—An Updated Review

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(2), P. 96 - 96

Published: Feb. 3, 2025

Background: Meroterpenoids represent a remarkably diverse class of natural secondary metabolites, some which are synthesized via terpenoid biosynthetic pathways. Over the past ten years, these compounds have gained interest because their wide range biological activities, such as anti-cholinesterase, COX-2 inhibitory, antibacterial, antiviral, antidiabetic, antioxidant, anti-inflammatory, antineoplastic, and cardioprotective properties. This review aims to consolidate recognized neuroprotective effects meroterpenoids from marine terrestrial fungi. Methods: Data compiled several databases, including PubMed, Science Direct, Scopus, Google Scholar, include articles published since 2000 using keywords “neuroprotective”, “fungi”, “mushroom”, “marine sponge”, “neurodegeneration”, “dementia” in connection with “meroterpenoids”. Results: modulate different cell signaling pathways exhibit often combined mechanisms action ameliorate neuronal damage dysfunction. Reported activities BACE1 inhibition, anti-inflammatory all potential treatment dementia associated neurodegenerative diseases Alzheimer’s Parkinson’s. Conclusions: be developed effective tools for neuropathological diseases. Ongoing research elucidate various remains essential requires further investigation.

Language: Английский

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Identification of Depression Subtypes in Parkinson's Disease Patients via Structural MRI Whole‐Brain Radiomics: An Unsupervised Machine Learning Study

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(2)

Published: Feb. 1, 2025

Current clinical evaluation may tend to lack precision in detecting depression Parkinson's disease (DPD). Radiomics features have gradually shown potential as auxiliary diagnostic tools identifying and distinguishing different subtypes of (PD), a radiomic approach that combines unsupervised machine learning has the identify DPD. Analyze imaging data 272 (PD) patients from PPMI dataset, along with 45 PD NACC dataset. Extract T1-weighted MRI images employ principal component analysis (PCA) for dimensionality reduction. Subsequently, apply four clustering methods including Gaussian mixture model (GMM), hierarchical clustering, K-means, partitioning around medoids (PAM) classify cases dataset into distinct subtypes. Identify high-risk DPD on basis time number progression, validate these findings using The subtype were divided training testing 7:3 ratio. Multiple logistic regression was conducted develop traditional subtype, which subsequently compared supervised constructed entire cohort. Finally, performance both models evaluated receiver operating characteristic (ROC) curves. In addition, decision tree (DT) based independent risk factors validated low-risk data. ROC curves employed this across datasets. PAM method demonstrates superior other three when clusters is 2. High-risk can be effectively distinguished A developed rapid-eye-movement behavior disorder, UPDRS I score, II ptau subgroups. This exhibits efficacy (AUC = 0.731) surpasses cohort 0.674). prediction had AUC values 0.853 0.81 subtypes, sensitivities 0.765 0.786, specificities 0.771 0.815, respectively. AUC, sensitivity, specificity nonhigh-risk 0.859, 0.654, 0.852, By structural radiomics biomarkers, UCA provide new insights pathophysiology support diagnosis high accuracy.

Language: Английский

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Fibrinogen-tau Aggregates Exacerbate Tau Pathology and Memory Deficits in Alzheimer’s Disease Model Mice

Neuroscience Bulletin, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

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Cellular Prion Protein and Amyloid-β Oligomers in Alzheimer’s Disease—Are There Connections?

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2097 - 2097

Published: Feb. 27, 2025

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Pathological deposits neurotoxin proteins within brain, such as amyloid-β and hyperphosphorylated tau tangles, are prominent features in AD. The prion protein (PrP) involved neurodegeneration via its conversion from normal cellular form (PrPC) to infection scrapie (PrPSc) form. Some studies indicated that post-translationally modified PrPC isoforms play a fundamental role AD pathological progression. Several have shown interaction Aβ oligomers (Aβos) with N-terminal residues region appears critical for neuronal toxicity. PrPC-Aβ binding always occurs brains never detected non-demented controls, aggregates restricted N-terminus PrPC. In this study, we aimed gather all recent information about connections between AD, potential clinical implications.

Language: Английский

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Intracellular anionic substances cause tau liquid-liquid phase separation

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: unknown, P. 151605 - 151605

Published: March 1, 2025

Language: Английский

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Novel strategies for targeting tau oligomers in neurodegenerative diseases

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(6)

Published: May 8, 2025

Language: Английский

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Tau and Depression: A Systematic Review

Published: Aug. 13, 2024

Objectives: The tau protein is essential for stabilizing microtubules. Changes in its phosphorylation are identified many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. hyperphosphorylation of the linked to various factors, including stress, which has a substantial impact on depressive illness. present study aimed systematically review studies that describe association between depression.Design: used PRISMA statement 2020 inclusion criterion articles describing individuals with depression. exclusion was lack comparison levels without depression.Results: A total 138 papers were identified, 21 ultimately included. One out every three included demonstrated statistical significance values depression group controls. Only one had an adequate sample but results any major significance.Conclusions: remains unclear. Studies sampling necessary answer this question.

Language: Английский

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Pilot Study for Deciphering Post-Translational Modifications and Proteoforms of Tau Protein by Capillary Electrophoresis-Mass Spectrometry

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 27, 2024

Abnormal accumulation of tau protein in the brain is one pathological hallmark Alzheimer's disease (AD). Many post-translational modifications (PTMs) are associated with development AD, such as phosphorylation, acetylation, and methylation. Therefore, a complete picture PTM landscape critical for understanding molecular mechanisms AD progression. Here, we offered pilot study combining two complementary analytical techniques, capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) reversed-phase liquid chromatography (RPLC)-MS/MS, bottom-up proteomics recombinant human tau-0N3R. We identified 50 phosphorylation sites tau-0N3R total, which about 25% higher than that from RPLC-MS/MS alone. CZE-MS/MS provided more (i.e., phosphorylation) modified peptides RPLC-MS/MS, its predicted electrophoretic mobility helped improve confidence peptides. developed highly efficient isoelectric focusing (cIEF)-MS technique to offer bird's-eye view proteoforms, 11 putative proteoforms carrying up nine lower pI values phosphorylated detected. Interestingly, under native-like cIEF-MS conditions, observed three dimers phosphate groups. The findings demonstrate CE-MS valuable characterization PTMs, even oligomerization.

Language: Английский

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