Mol Neurobiol. 2012 Aug 31. [Epub ahead of print]
Yasuda T, Nakata Y, Mochizuki H.
Source
Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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.
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