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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
  • Published:
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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.

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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

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Acknowledgments

This work was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO); Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan; the Research Grant for Longevity Sciences from the Ministry of Health, Labour and Welfare of Japan; and grants (#S0801035) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

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  1. Department of Neurology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 228-8555, Japan

    Toru Yasuda & Hideki Mochizuki

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  1. Toru Yasuda
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Correspondence to Toru Yasuda or Hideki Mochizuki.

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Yasuda, T., Mochizuki, H. The regulatory role of α-synuclein and parkin in neuronal cell apoptosis; possible implications for the pathogenesis of Parkinson’s disease. Apoptosis 15, 1312–1321 (2010). https://doi.org/10.1007/s10495-010-0486-8

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