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.

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

“…S6). Hence, these findings suggest that AMPK might mediate DAergic cell death upon MPP + treatment primarily through excessive autophagy, in keeping with the controversial view of apoptosis in PD (38). Accordingly, in PIKE-null and Fyn-KO mice, overexpression of AMPK-DN suppressed MPTP-induced autophagy in the substantia nigra, leading to improved DAergic neuronal survival and motor function (Fig.…”

Dynamic Aspects of Amyloid Fibrils of α-Synuclein Related to the Pathogenesis of Parkinson’s Disease

“…Neuropathological hallmarks of PD are a prominent loss of dopaminergic neurons in the substantia nigra pars compacta and formation of the protein inclusions called Lewy bodies (LB) and Lewy neurites (LN) in neuronal somas and processes, respectively [1]. The major component in these inclusions is α-synuclein (αSyn), which is a 140 amino acid protein of unknown function, usually abundant in presynaptic terminals of nerve cells [2].…”

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

“…1 Genome-wide studies have identified SNCA and MAPT, genes encoding α-synuclein (α-Syn) and Tau, respectively, as having strong association to the genesis of PD. [2][3][4] Although the precise etiology of PD remains a mystery, SNCA amplifications and mutations directly link α-Syn dysfunction to disease causation, 5,6 firmly establishing a role for α-Syn in sporadic and familial PD, respectively. α-Syn can be phosphorylated at several sites, 7 and the predominance of α-Syn phosphorylated at serine 129 (S129) in Lewy bodies 8 suggests its phosphorylation status at S129 has an important pathological role.…”