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

Abstract

Background: α-Synuclein (α-syn) is a small presynaptic protein ubiquitously distributed in the central and peripheral nervous system. In normal conditions α-syn is found in soluble form, while in Parkinson’s disease (PD) it becomes phosphorylated, aggregates, and combines with other proteins to form Lewy bodies. Objective: To study in non-human primates whether α-syn expression is affected by age and neurotoxin challenge. Methods: 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 MPTP. Four untreated rhesus monkeys (n=3, 5-8 years old; n=1, 24 years old) were used as controls. Three months post-MPTP the animals were necropsied by transcardiac perfusion, their brains extracted and processed with immunohistochemical methods. Results: Quantification of tyrosine hydroxylase (TH)-ir nigral neurons showed a significant and similar decrease in the side ipsilateral to MPTP administration in young and old animals. Optical density of TH-ir in the striatum presented a 60-70% loss compared to the contralateral side. α-Syn immune-reactivity was present in both ipsiand contralateral MPTP-treated nigra and striatum, 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 substantia nigra in the aged animals. TH and α-syn immunofluorescence confirmed the loss of nigral TH-positive 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 mainly present in GABAergic fibers. Conclusion: Our results demonstrate that three months post MPTP α-syn expression in the substantia nigra is mainly present in GABAergic fibers. It also shows that α-syn expression in the nigrostriatal system of rhesus monkeys increases with age, but not after neurotoxin-induced dopaminergic nigral cell loss.