Apoptosis

, Volume 15, Issue 11, pp 1312–1321

The regulatory role of α-synuclein and parkin in neuronal cell apoptosis; possible implications for the pathogenesis of Parkinson’s disease

Apoptosis in the Aging Brain

DOI: 10.1007/s10495-010-0486-8

Cite this article as:
Yasuda, T. & Mochizuki, H. Apoptosis (2010) 15: 1312. doi:10.1007/s10495-010-0486-8

Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder beyond Alzheimer’s disease, affecting approximately 1% of people over the age of 65. The major pathological hallmarks of PD are significant loss of nigrostriatal dopaminergic (DA) neurons and the presence of intraneuronal protein inclusions termed Lewy bodies. Sporadic cases represent more than 90% of total patients with PD, while there exist several inherited forms caused by mutations in single genes. Identification and characterization of these causative genes and their products can help us understand the molecular mechanisms of DA neuronal cell death and design new approaches to treat both the inherited and sporadic forms of PD. Based on the finding that a point mutation in the gene encoding α-synuclein (αSyn) protein causes a rare familial form of PD, PARK1, it is now confirmed that αSyn is a major component of Lewy bodies in patients with sporadic PD. Abnormal accumulation of αSyn protein is considered a neurotoxic event in the development of PD. PARK4, another dominantly inherited form of familial PD, is caused by duplication or triplication of the αSyn gene locus. This genetic mutation results in the production of large amounts of wild-type αSyn protein, supporting the αSyn-induced neurodegeneration hypothesis. On the other hand, the recessively inherited early-onset Parkinsonism is caused in about half of the cases with loss-of-function mutations in PARK2, which encodes E3 ubiquitin ligase parkin in the ubiquitin–proteasome system. These findings have shed light on DA neurodegeneration caused by accumulation of toxic protein species that can be degraded and/or detoxicated through parkin activity. In this review, we will focus on the regulatory roles of αSyn and parkin proteins in DA neuronal cell apoptosis and provide evidence for the possible therapeutic action of parkin in sporadic patients with PD.

Keywords

Parkinson’s disease α-synuclein Parkin Dopaminergic neurons Apoptosis 

Abbreviations

αSyn

α-synuclein

DA

Dopaminergic

EGF

Epidermal growth factor

EGFR

EGF receptor

JNK

c-Jun N-terminal kinase

MAO

Monoamine oxidase

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NSC

Neural stem cell

OB

Olfactory bulb

Pael-R

Parkin-associated endothelin receptor-like receptor

PD

Parkinson’s disease

rAAV

Recombinant adeno-associated virus

SNpc

Substantia nigra pars compacta

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of NeurologyKitasato University School of MedicineSagamiharaJapan

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