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

Aggregated alpha-synuclein (alpha-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 alpha-synuclein exist, including phosphorylated and nitrated forms. It is unclear which alpha-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant alpha-synuclein PTMs in postmortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three alpha-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 alpha-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures, followed by nY39 alpha-synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 alpha-synuclein in MSA. Quantification of the LB scores revealed that pS129 alpha-synuclein was the dominant and earliest alpha-synuclein PTM, followed by nY39 alpha-synuclein, while lower amounts of pSer87 alpha-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.