Increased α-synuclein phosphorylation and nitration in the aging primate substantia nigra

Post-translational modifications of alpha-synuclein occur in the brain of patients affected by Parkinson's disease and other alpha-synucleinopathies, as indicated by the accumulation of Lewy inclusions containing phosphorylated (at serine 129) and nitrated alpha-synuclein. Here we found that phospho-Ser 129 and nitrated alpha-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 alpha-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 alpha-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 alpha-synuclein, supporting a relationship between higher levels of normal protein and enhanced phosphorylation/nitration. Other mechanisms were also identified that likely contribute to alpha-synuclein modifications. In particular, increased expression of Polo-like kinase 2 within neurons of older animals could contribute to phospho-Ser 129 alpha-synuclein production. Data also indicate that a pro-oxidant environment characterizes older neurons and favors alpha-synuclein nitration. Aging is an unequivocal risk factor for human alpha-synucleinopathies. These findings are consistent with a mechanistic link between aging, alpha-synuclein abnormalities and enhanced vulnerability to neurodegenerative processes. Cell Death and Disease (2012) 3, e315; doi:10.1038/cddis.2012.50; published online 31 May 2012