α-Synuclein and neuronal cell death

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ~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 α-synuclein (αSyn). Missense mutations in αSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type αSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of αSyn protein is considered responsible for the DA neuronal death in PD. Normally, αSyn 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 αSyn. The extracellular αSyn 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 αSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on αSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating αSyn.

Fig. 1

Schematic representation of molecular events and potential therapeutic targets associated with abnormal αSyn in PD. The molecular events that are reduced in PD and/or potentially neuroprotective, or considered to be neurotoxic, are shown in blue, or red arrows and inhibitory lines, respectively. Accumulation of αSyn oligomer, which can be modulated by several post-translational modification(s) of αSyn, leads to reduced neuronal cell viability by inhibiting ER-Golgi trafficking, autophagy, and/or proteasome. Mitochondrial translocation of αSyn induces production of ROS and RNS, further enhancing oxidative/nitrosative modification of αSyn. Oligomerized αSyn species can also be secreted into extracellular space, which might induce inflammatory glial reactions, pore formation on plasma membrane, or transmission to the neighboring neuronal cells to promote Lewy formation and/or cell death. These neurotoxic events can be ameliorated by several ways as indicated (also see the main text)

Fig. 2

AAV vector-mediated expression of foreign gene in mouse brain. a The AAV vector can be injected stereotaxically into the SN of mice. b–e Representative images for the AAV vector-mediated overexpression of human αSyn (hαSyn) or GFP in DA cells. Nigral sections of the AAV-GFP- (b, d) or AAV-hαSyn-injected mice (c, e) were immunostained for GFP (GFP; b, d; shown in green) or hαSyn (c, e; green) and tyrosine hydroxylase (TH; b–e; red; merged with anti-GFP or hαSyn, yellow). Images for DAPI are also merged (d, e; blue). Note that the overexpression of hαSyn caused a profound loss of DA cell bodies with neuritic pathology. The overexpressed hαSyn was localized to nucleus and cytoplasm in a heterogeneous pattern in the remaining DA cells, while GFP distributed uniformly. Scale bars: (b, c) 20 μm and (d, e) 10 μm