Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy

Version 1 : Received: 10 January 2022 / Approved: 12 January 2022 / Online: 12 January 2022 (14:31:13 CET)

How to cite: Sonustun, B.; Altay, F.M.; Strand, C.; Hondhamuni, G.; Warner, T.T.; Lashuel, H.A.; Bandopadhyay, R. Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy. Preprints 2022, 2022010174 (doi: 10.20944/preprints202201.0174.v1). Sonustun, B.; Altay, F.M.; Strand, C.; Hondhamuni, G.; Warner, T.T.; Lashuel, H.A.; Bandopadhyay, R. Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy. Preprints 2022, 2022010174 (doi: 10.20944/preprints202201.0174.v1).

Abstract

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Keywords

alpha-synuclein; post-translational modifications; Parkinson’s disease; Multiple system atrophy; Lewy bodies; Lewy neurites; Glial cytoplasmic inclusions; phosphorylation; nitration; immunohistochemistry

Subject

LIFE SCIENCES, Other

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