Increased α-synuclein phosphorylation and nitration in the aging primate substantia nigra.
Post-translational modifications of α-synuclein occur in the brain of patients affected by Parkinson's disease and other α-synucleinopathies, as indicated by the accumulation of Lewy inclusions containing phosphorylated (at serine 129) and nitrated α-synuclein. Here we found that phospho-Ser 129 and nitrated α-synuclein are also formed within dopaminergic neurons of the monkey substantia nigra as a result of normal aging. Dopaminergic cell bodies immunoreactive for phospho-Ser 129 and nitrated α-synuclein were rarely seen in adult mature animals but became significantly more frequent in the substantia nigra of old primates. Dual labeling with antibodies against phospho-Ser 129 and nitrated α-synuclein revealed only limited colocalization and mostly stained distinct sub-populations of dopaminergic neurons. Age-related elevations of modified protein paralleled an increase in the number of neurons immunoreactive for unmodified α-synuclein, supporting a relationship between higher levels of normal protein and enhanced phosphorylation/nitration. Other mechanisms were also identified that likely contribute to α-synuclein modifications. In particular, increased expression of Polo-like kinase 2 within neurons of older animals could contribute to phospho-Ser 129 α-synuclein production. Data also indicate that a pro-oxidant environment characterizes older neurons and favors α-synuclein nitration. Aging is an unequivocal risk factor for human α-synucleinopathies. These findings are consistent with a mechanistic link between aging, α-synuclein abnormalities and enhanced vulnerability to neurodegenerative processes.
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
A L
AL
McCormack
S K
SK
Mak
D A
DA
Di Monte
D000375:Aging / Q000378:metabolism*; D000818:Animals; D006801:Humans; D009474:Neurons / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012453:Saimiri; D012694:Serine / Q000235:genetics; D013378:Substantia Nigra / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D009574:Nitro Compounds; D051844:alpha-Synuclein; D012694:Serine