Preprint Hypothesis Version 2 Preserved in Portico This version is not peer-reviewed

Role of a-Synuclein in Cell Biology: A Hypothesis and its Implications in Neurodegenerative Diseases

Version 1 : Received: 18 April 2021 / Approved: 22 April 2021 / Online: 22 April 2021 (10:47:07 CEST)
Version 2 : Received: 31 December 2021 / Approved: 10 January 2022 / Online: 10 January 2022 (12:23:19 CET)

How to cite: Minda, R. Role of a-Synuclein in Cell Biology: A Hypothesis and its Implications in Neurodegenerative Diseases. Preprints 2021, 2021040606 (doi: 10.20944/preprints202104.0606.v2). Minda, R. Role of a-Synuclein in Cell Biology: A Hypothesis and its Implications in Neurodegenerative Diseases. Preprints 2021, 2021040606 (doi: 10.20944/preprints202104.0606.v2).

Abstract

I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is to modulate membrane fluidity by a process wherein it goes through a conformation cycle driven by a flux of energy from mitochondria. It is the range of toxic a-syn produced during aberrant phase transition reaction that is responsible for pathology, not the normal a-syn that reenters the conformation cycle, thereby, resolving the paradox of the Janus-face of a-syn.

Keywords

Parkinson’s disease; alpha-synuclein; Lewy bodies; phase transition; thermodynamics; and mitochondria

Subject

LIFE SCIENCES, Biophysics

Comments (1)

Comment 1
Received: 10 January 2022
Commenter: Renu Minda
Commenter's Conflict of Interests: Author
Comment: The current version elaborates on the effect of phase transition reaction catalysed by alpha-
synuclein that occasionally ejects its toxic forms. It is hypothesized that these aberrant alpha-synuclein
molecules but not its unaltered cytosolic forms are the cause of neurodegeneration leading to
prodromal stage of PD and other synucleinopathies. If the hypothesis turns out correct,
reassessment of strategies for future drug design may be necessary.
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