Motor impairment and aberrant production of neurochemicals in human α-synuclein A30P+A53T transgenic mice with α-synuclein pathology

Missense point mutations, duplication and triplication in the alpha-synuclein (alpha SYN) gene have been identified in familial Parkinson's disease (PD). Familial and sporadic PD show common pathological features of alpha SYN pathologies, e.g., Lewy bodies (LBs) and Lewy neurites (LNs), and a loss of dopaminergic neurons in the substantia nigra that leads to motor disturbances. To elucidate the mechanism of alpha SYN pathologies, we generated Tg alpha SYN transgenic mice overexpressing human alpha SYN with double mutations in A30P and A53T. Human alpha SYN accumulated widely in neurons, processes and aberrant neuronal inclusion bodies. Sarcosyl-insoluble alpha SYN, as well as phosphorylated, ubiquitinated and nitrated alpha SYN, was accumulated in the brains. Significantly decreased levels of dopamine (DA) were recognized in the striatum. Motor impairment was revealed in a rotarod test. Thus, Tg alpha SYN is a useful model for analyzing the pathological cascade from aggregated alpha SYN to motor disturbance, and may be useful for drug trials. (C) 2008 Published by Elsevier B.V.