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Abstract
Our previous cryogenic electron microscopy (cryoEM) analysis showed that the core structures of α-synuclein filaments accumulated in brains of patients diagnosed with dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) patients are different. We analyzed the post-translational modifications (PTMs) in these filaments , and examined their relationship with the core filament structures and pathological features. Besides the common PTMs in MSA and DLB filaments, acetylation, methylation, oxidation and phosphorylation were frequently detected in MSA filaments, but not in DLB filaments. Furthermore, in DLB filament cases, the processing occurred at the C-terminal side of Asp at 119 residue and Asn at 122 residue, while in MSA cases, the processing occurred at multiple sites between residues 109–123. We have previously reported that PTMs in tau filaments depend on the filament core structure. This was considered to apply to α-synuclein filaments as well. As an example, PTMs including processing sites detected in α-synuclein filaments in early-onset DLB (an atypical form, now named juvenile-onset α-synucleinopathy) brain also supported this idea. These suggests that PTMs appeared to be closely related to the specific filament core structures.
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1 Tokyo Metropolitan Institute of Medical Science, Department of Brain and Neurosciences, Tokyo, Japan (GRID:grid.272456.0)
2 National Center of Neurology and Psychiatry, Department of Clinical Laboratory and Internal Medicine, Tokyo, Japan (GRID:grid.419280.6) (ISNI:0000 0004 1763 8916); Mihara Memorial Hospital, Department of Neurology and Brain Bank, Isesaki, Japan (GRID:grid.471636.1)
3 Tokyo Metropolitan Institute of Geriatrics and Gerontology, Department of Neuropathology (Brain Bank for Aging Research), Tokyo, Japan (GRID:grid.471636.1)
4 Sagamihara National Hospital, Division of Neurology, Kanagawa, Japan (GRID:grid.415689.7) (ISNI:0000 0004 0642 7451)
5 Aichi Medical University, Institute for Medical Science of Aging, Nagakute, Japan (GRID:grid.411234.1) (ISNI:0000 0001 0727 1557)
6 Tokyo Metropolitan Institute of Geriatrics and Gerontology, Department of Neuropathology (Brain Bank for Aging Research), Tokyo, Japan (GRID:grid.411234.1)
7 Tokyo Metropolitan Institute of Geriatrics and Gerontology, Department of Neuropathology (Brain Bank for Aging Research), Tokyo, Japan (GRID:grid.411234.1); University of Osaka, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971)