α-Synuclein and Neuronal Cell Death

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting similar to 1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of alpha-synuclein (alpha Syn). Missense mutations in alpha Syn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type alpha Syn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of alpha Syn protein is considered responsible for the DA neuronal death in PD. Normally, alpha Syn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal alpha Syn. The extracellular alpha Syn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of alpha Syn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on alpha Syn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating alpha Syn.