Abstract
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.
Highlights
Aging is an unequivocal Parkinson’s disease (PD) risk factor, the precise mechanisms by which neuronal susceptibility to degenerative processes is augmented by age remain unclear.[12]
Members of the Polo-like kinase (PLK) protein family and, in particular, PLK2 have an important role in a-synuclein phosphorylation at Ser129.5,19,20 Using immunohistochemistry to identify and count PLK2-expressing neurons, we found that the number of cells displaying robust staining was 43-fold greater in the substantia nigra of old as compared with mature monkeys (Figures 2a–c)
The effects of aging on nigral dopaminergic neurons were assessed after immunostaining monkey midbrain sections with specific antibodies against unmodified, phosphorylated or nitrated a-synuclein
Summary
Aging is an unequivocal PD risk factor, the precise mechanisms by which neuronal susceptibility to degenerative processes is augmented by age remain unclear.[12]. Subsequent studies reported an increase in the number, optical density and fluorescence intensity of a-synuclein-immunoreactive neurons as a function of age in the substantia nigra but not the ventral tegmental area of humans and rhesus monkeys.[14,15] experimental evidence indicates that age-related a-synuclein changes are rather unique to primates as levels of this protein decline in the mouse substantia nigra.[16] The primate substantia nigra is highly vulnerable to both a-synuclein pathology and neurodegeneration, raising the intriguing possibility that this enhanced susceptibility is due, at least in part, to age-related a-synuclein elevation. The number of neuronal cell bodies immunoreactive for normal, phospho-Ser 129 and nitrated a-synuclein was compared in the substantia nigra of young adult versus old squirrel monkeys. Results are consistent with the interpretation that besides the increase in normal a-synuclein levels enhanced kinase expression and pro-oxidant/nitrative conditions contribute to the production of phospho-Ser 129 and nitrated a-synuclein, respectively, in older nigral neurons
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