A Nuclear-Cytoplasmic Trafficking Hypothesis of Multiple System Atrophy: TPPP/p25α Mislocalization as the Primary Trigger of Neurodegeneration

A Nuclear-Cytoplasmic Trafficking Hypothesis of Multiple System Atrophy: TPPP/p25α Mislocalization as the Primary Trigger of Neurodegeneration | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 26 June 2025 V2 Latest version Share on A Nuclear-Cytoplasmic Trafficking Hypothesis of Multiple System Atrophy: TPPP/p25α Mislocalization as the Primary Trigger of Neurodegeneration Author : Pavel Solodukhin 0009-0000-8191-0177 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175079870.08917153/v2 299 views 107 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Multiple System Atrophy (MSA) is a rapidly progressive and fatal neurodegenerative disorder characterized by selective oligodendrocyte pathology, glial cytoplasmic inclusions (GCIs), and early autonomic failure. Despite the intense focus on α-synuclein aggregation, clinical and molecular inconsistencies persist, most notably, the selective vulnerability of oligodendrocytes and the failure of α-synuclein-targeted therapies in mid-to-late-stage trials. We propose a novel hypothesis centered on damage induced by chronic iron-induced oxidative stress to the nuclear pore complex (NPC), leading to impaired recognition of the nuclear localization signal (NLS) of TPPP/p25α by importin α/β. As a result, TPPP/p25α is mislocalized from the nucleus and myelin to the perinuclear cytoplasm. In this aberrant location, TPPP/p25α catalyzes the conformational conversion of extracellular α-synuclein into a stable prion-like strain, initiating GCI formation and subsequent neurodegeneration. This model offers a unifying explanation for long-standing pathophysiological paradoxes and requires a strategic shift in therapeutic development: 1) restoration of nuclear import fidelity and NPC integrity, 2) inhibition of pathological TPPP/p25α-α-synuclein interactions, and only subsequently 3) α-synuclein clearance at later stages. If validated, this hypothesis could reframe the future of MSA therapy and diagnostics. Supplementary Material File (msa hypothesis 2606 updated.pdf) Download 1.34 MB Information & Authors Information Version history V1 Version 1 24 June 2025 V2 Version 2 26 June 2025 Copyright This work is licensed under a Creative Commons Attribution 4.0 International License Keywords alpha-synuclein strain selectivity multiple system atrophy nucleocytoplasmic transport dysfunction therapeutic target identification tppp/p25α mislocalization Authors Affiliations Pavel Solodukhin 0009-0000-8191-0177 [email protected] View all articles by this author Metrics & Citations Metrics Article Usage 299 views 107 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Pavel Solodukhin. A Nuclear-Cytoplasmic Trafficking Hypothesis of Multiple System Atrophy: TPPP/p25α Mislocalization as the Primary Trigger of Neurodegeneration. Authorea . 26 June 2025. 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