α-Synuclein Expression Is Preserved in Substantia Nigra GABAergic Fibers of Young and Aged Neurotoxin-Treated Rhesus Monkeys

Abstract

α-Synuclein (α-syn) is a small presynaptic protein distributed ubiquitously in the central and peripheral nervous system. In normal conditions, α-syn is found in soluble form, while in Parkinson’s disease (PD) it may phosphorylate, aggregate, and combine with other proteins to form Lewy bodies. The purpose of this study was to evaluate, in nonhuman primates, whether α-syn expression is affected by age and neurotoxin challenge. Young adult (n = 5, 5–10 years old) and aged (n = 4, 23–25 years old) rhesus monkeys received a single unilateral carotid artery injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Three months post-MPTP the animals were necropsied by transcardiac perfusion, and their brains extracted and processed with immunohistochemical methods. Quantification of tyrosine hydroxylase (TH)-positive substantia nigra (SN) neurons showed a significant 80–89% decrease in the side ipsilateral to MPTP administration in young and old animals. Optical density of TH- immunoreactivity (-ir) in the caudate and putamen presented a 60–70% loss compared with the contralateral side. α-Syn-ir was present in both ipsi- and contra- lateral MPTP-treated nigra, caudate, and putamen, mostly in fibers; its intracellular distribution was not affected by age. Comparison of α-syn-ir between MPTP-treated young and aged monkeys revealed significantly higher optical density for both the ipsi- and contralateral caudate and SN in the aged animals. TH and α-syn immunofluorescence confirmed the loss of nigral TH-ir dopaminergic neurons in the MPTP-treated side of intoxicated animals, but bilateral α-syn expression. Colabeling of GAD67 and α-syn immunofluorescence showed that α-syn expression was present mainly in GABAergic fibers. Our results demonstrate that, 3 months post unilateral intracarotid artery infusion of MPTP, α-syn expression in the SN is largely present in GABAergic fibers, regardless of age. Bilateral increase of α-syn expression in SN fibers of aged, compared with young rhesus monkeys, suggests that α-syn-ir may increase with age, but not after neurotoxin-induced dopaminergic nigral cell loss.