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 α-synuclein (αSYN) gene have been identified in familial Parkinson's disease (PD). Familial and sporadic PD show common pathological features of αSYN 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 αSYN pathologies, we generated TgαSYN transgenic mice overexpressing human αSYN with double mutations in A30P and A53T. Human αSYN accumulated widely in neurons, processes and aberrant neuronal inclusion bodies. Sarcosyl-insoluble αSYN, as well as phosphorylated, ubiquitinated and nitrated αSYN, 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, TgαSYN is a useful model for analyzing the pathological cascade from aggregated αSYN to motor disturbance, and may be useful for drug trials.