α‐Synuclein Up‐Regulation in Substantia Nigra Dopaminergic Neurons Following Administration of the Parkinsonian Toxin MPTP

Mutations in α‐synuclein cause a form of familial Parkinson’s disease (PD), and wild‐type α‐synuclein is a major component of the intraneuronal inclusions called Lewy bodies, a pathological hallmark of PD. These observations suggest a pathogenic role for α‐synuclein in PD. Thus far, however, little is known about the importance of α‐synuclein in the nigral dopaminergic pathway in either normal or pathological situations. Herein, we studied this question by assessing the expression of synuclein‐1, the rodent homologue of human α‐synuclein, in both normal and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐intoxicated mice. In normal mice, detectable levels of synuclein mRNA and protein were seen in all brain regions studied and especially in ventral midbrain. In the latter, there was a dense synuclein‐positive nerve fiber network, which predominated over the substantia nigra, and only few scattered synuclein‐positive neurons. After a regimen of MPTP that kills dopaminergic neurons by apoptosis, synuclein mRNA and protein levels were increased significantly in midbrain extracts; the time course of these changes paralleled that of MPTP‐induced dopaminergic neurodegeneration. In these MPTP‐injected mice, there was also a dramatic increase in the number of synuclein‐immunoreactive neurons exclusively in the substantia nigra pars compacta; all synuclein‐positive neurons were tyrosine hydroxylase‐positive, but none coexpressed apoptotic features. These data indicate that synuclein is highly expressed in the nigrostriatal pathway of normal mice and that it is up‐regulated following MPTP‐induced injury. In light of the synuclein alterations, it can be suggested that, by targeting this protein, one may modulate MPTP neurotoxicity and, consequently, open new therapeutic avenues for PD.