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

Cells

Hilal A. Lashuel¹  Melek Firat Altay¹  Catherine Strand²  Geshanthi Hondhamuni²  Berkiye Sonustun³  Kirsten Ebanks³  Rina Bandopadhyay³  Thomas T. Warner³ 

[1] Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland;Queen Square Brain Bank, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK;Reta Lila Weston Institute and Department of Movement Neuroscience, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK;

关键词: alpha-synuclein;    post-translational modifications;    Parkinson’s disease;    multiple system atrophy;    Lewy bodies;    Lewy neurites;   

DOI  :  10.3390/cells11050906

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown