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

Berkiye Sonustun,Rina Bandopadhyay,Melek Firat Altay,Kirsten Ebanks,Catherine Strand,Hilal A Lashuel,Thomas T Warner,Geshanthi Hondhamuni

doi:10.3390/cells11050906

Abstract

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

Highlights

Parkinson’s disease (PD) is the second most prevalent chronic progressive neurodegenerative disorder, affecting more than 1% of the population above 60 years of age [1]
Biochemical fractionation from postmortem brains reported that over 90% of the insoluble α-synuclein proteins found in dementia with Lewy body (DLB) cases are phosphorylated at S129 compared to the 4% seen in healthy brains [17], thereby implicating phosphorylation at this residue as a potential key event in α-synuclein pathology formation, spreading, or clearance
We report that phosphorylation at Ser129 (pS129) α-synuclein is a major modification in idiopathic PD (IPD) and multiple system atrophy (MSA), followed by nY39 α-synuclein; the lowest numbers of Lewy bodies (LBs)/glial cytoplasmic inclusions (GCIs) positive for pS87 α-synuclein were noted in the two diseases

Summary

Introduction

Parkinson’s disease (PD) is the second most prevalent chronic progressive neurodegenerative disorder, affecting more than 1% of the population above 60 years of age [1]. Degeneration of the dopaminergic nigrostriatal system is a prominent pathological feature of PD, leading to impaired dopaminergic neurotransmission within the basal ganglia. The presence of aggregated α-synuclein within cytoplasmic Lewy bodies (LBs) and dystrophic Lewy neurites (LNs) is a common pathological feature at postmortem [7]. Braak et al [8] have proposed a model wherein it is suggested that LB pathology in PD arises in the dorsal motor nucleus of the vagus or the anterior olfactory nucleus before affecting the nigra and the limbic regions, followed by spreading in higher cortical regions [8]. Increasing evidence suggests that this occurs via the putative prion-like spread of α-synuclein [9]

Objectives

Methods

Findings

Discussion

Conclusion