Alpha-Synuclein: from structural biology and conformational dynamics to molecular mechanisms of neurotoxicity

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Abstract

Objective. To systematize current knowledge on the structural organization, conformational dynamics, and mechanisms of membrane toxicity of alpha-synuclein, as well as to analyze the role of age-associated impairment of proteostasis systems in the pathogenesis of synucleinopathies.

Material and methods. A literature review was conducted covering publications indexed in PubMed, Scopus, Web of Science, and eLibrary databases for the period 2010 – 2026.

Key Findings. Soluble prefibrillar oligomers, capable of integrating into the lipid bilayer and forming annular pores, possess the greatest damaging potential in synucleinopathies. An original hypothesis is proposed for the formation of a transmembrane pore based on the parallel stacking of NAC domains without register shifting and lateral association of subunits forming a hydrophobic interface, geometrically classified as a composite prismatoid or scutoid.

Conclusion. Understanding the molecular mechanisms of oligomer membrane toxicity and age-related proteostasis failure opens new horizons for the development of pathogenetic therapies and substantiates the implementation of highly sensitive methods for early preclinical diagnosis.

About the authors

Nataliya A. Kolotieva

Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”

Author for correspondence.
Email: kolotyeva.n.a@neurology.ru
ORCID iD: 0000-0002-7853-6222

Leading Researcher; Doctor of Medical Sciences

Russian Federation, Volokolamskoye Shosse, 80, Moscow, 125367

Vladimir V. Salmina

Federal State Autonomous Educational Institution of Higher Education “Bauman Moscow State Technical University”

Email: vsalmin@gmail.com
ORCID iD: 0000-0003-4441-9025

Professor; Doctor of Physical and Mathematical Sciences, Professor

Russian Federation, 2nd Baumanskaya Street, 5, build. 1, Moscow, 105005

Polina V. Guk

Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”

Email: bf30h36@gmail.com
ORCID iD: 0009-0005-9385-3452

Postgraduate Student, Research Laboratory Assistant

Russian Federation, Volokolamskoye Shosse, 80, Moscow, 125367

Valeria S. Voronina

Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”

Email: voronina.vlrs@gmail.com
ORCID iD: 0009-0009-4665-1961

Postgraduate Student, Research Laboratory Assistant

Russian Federation, Volokolamskoye Shosse, 80, Moscow, 125367

Alexey V. Rossokhin

Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”

Email: rossokhin@neurology.ru
ORCID iD: 0000-0001-7024-7461

Leading Researcher; Candidate of Physical and Mathematical Sciences

Russian Federation, Volokolamskoye Shosse, 80, Moscow, 125367

Irena V. Salmina

Federal State Autonomous Educational Institution of Higher Education “Siberian Federal University”

Email: irenairenairena0202@mail.ru
ORCID iD: 0009-0005-4700-2366

2nd year graduate student

Russian Federation, Svobodny Ave., 79, Krasnoyarsk, 660041

Pavel P. Tregub

Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”

Email: pfiza_asmu@mail.ru

Senior Researcher; Doctor of Medical Sciences

Russian Federation, Volokolamskoye Shosse, 80, Moscow, 125367

Dmitry A. Kudlay

I.M. Sechenov First Moscow State Medical University (Sechenov University); Lomonosov Moscow State University

Email: D624254@gmail.com
ORCID iD: 0000-0003-1878-4467

Research Director, Professor of the Department of Pharmacology, Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University); Deputy Dean for Scientific and Technological Development of the Faculty of Bioengineering and Bioinformatics, Senior Researcher, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University. Doctor of Medical Sciences, Сorresponding member of the Russian Academy of Sciences

Russian Federation, Trubetskaya St., 8, building 2, Moscow, 119048; Leninskie Gory, GSP-1, Moscow, 119991

Sergey N. Illarioshkin

Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”

Email: snillario@gmail.com
ORCID iD: 0000-0002-2704-6282

Director of the Brain Institute, Deputy Director; Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences

Russian Federation, Volokolamskoye Shosse, 80, Moscow, 125367

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