A30P alpha-synuclein impairs dopaminergic fiber regeneration and interacts with L-DOPA replacement in MPTP-treated mice

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta (SNpc). alpha-synuclein (alpha syn) has been linked to the pathophysiology of PD, because of its mutations causing familial PD and its accumulation in brains of patients with familial and sporadic PD. Dopamine (DA) replacement is the most effective therapy for ameliorating the motor symptoms of PD; however, it remains controversial whether DA-replacement boosts regeneration in the dopaminergic system or accelerates disease progression and enhances neuronal loss. Here, we studied the effect of chronic L-DOPA treatment on dopaminergic neurons in wild-type (WT) and A30P alpha syn transgenic mice after MPTP treatment. Acute MPTP intoxication induced degeneration of dopaminergic neurons in both WT and A30P alpha syn transgenic mice. A strong regeneration of dopaminergic fibers at 90 days after MPTP was observed in WT mice. In contrast, regeneration was less pronounced in A30P alpha syn mice. Chronic L-DOPA treatment after MPTP intoxication did not only reduce the regeneration of nigrostriatal fibers but also led to an increased apoptotic gene-expression profile in the SNpc and to a decline of TH-positive neurons in A30P alpha syn. Our findings reveal that the presence of A30P alpha syn inhibits the regeneration of nigrostriatal dopaminergic fibers, and that L-DOPA treatment might interact with the pathogenesis in PD. (C) 2011 Elsevier Inc. All rights reserved.