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Molecular Neurobiology

, Volume 47, Issue 2, pp 466–483

First Online: 31 August 2012Received: 09 August 2012Accepted: 12 August 2012

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.

Keywordsα-Synuclein Apoptosis Dopaminergic neuron Neuroprotection Parkinson’s disease Substantia nigra AbbreviationsAAVAdeno-associated virus

ACDAutophagic cell death

αSynα-Synuclein

CaMKIIαCalcium-calmodulin-dependent protein kinase IIα

CMAChaperone-mediated autophagy

CSPαCysteine-string protein-α

DADopaminergic

DLBDementia with Lewy bodies

DMT1Divalent metal transporter 1

Dnmt1DNA methyltransferase 1

EREndoplasmic reticulum

GCaseGlucocerebrosidase

GDNFGlial cell line-derived neurotrophic factor

HDACHistone deacetylase

Hsc70Heat shock cognate 70

LRRK2Leucine-rich repeat kinase 2

MPTP1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

mTORMammalian target of rapamycin

OBOlfactory bulb

PCDProgrammed cell death

PDParkinson’s disease

PP2APhosphoprotein phosphatase A2

RIPReceptor-interacting protein

RNSReactive nitrogen species

ROSReactive oxygen species

SNSubstantia nigra

SNAP-25Synaptosomal-associated protein of 25 K

SNARESoluble N-ethylmaleimide-sensitive factor attachment protein receptor

SNpcSubstantia nigra pars compacta

THTyrosine hydroxylase

UCH-L1Ubiquitin carboxy-terminal hydrolase-L1

VPAValproic acid

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Author: Toru Yasuda - Yasuto Nakata - Hideki Mochizuki

Source: https://link.springer.com/







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