Is malfunction of the ubiquitin proteasome system the primary cause of α-synucleinopathies and other chronic human neurodegenerative disease?

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1782

Review

Bedford, Lynn¹  Hay, David¹  Paine, Simon¹  Rezvani, Nooshin¹  Mee, Maureen¹  Lowe, James¹  Mayer, R. John¹ 

[1] Univ Nottingham, Sch Med, Queens Med Ctr, Sch Biomed Sci & Mol Med Sci, Nottingham NG7 2UH, England

关键词: Ubiquitin;    26S proteasome;    Neurodegeneration;    Dementia with Lewy bodies;    Parkinson's disease;   

DOI  :  10.1016/j.bbadis.2008.10.009

来源: Elsevier

【 摘 要 】

Neuropathological investigations have identified major hallmarks of chronic neurodegenerative disease. These include protein aggregates called Lewy bodies in dementia with Lowy bodies and Parkinson's disease. Mutations in the alpha-synuclein gone have been found in familial disease and this has led to intense focused research in vitro and in transgenic animals to mimic and Understand Parkinson's disease. A decade of transgenesis has lead to overexpression of wild type and mutated alpha-synuclein, but without faithful reproduction of human neuropathology and movement disorder. In particular, widespread regional neuronal cell death in the substantia nigra associated with human disease has not been described. The intraneuronal protein aggregates (inclusions) in all of the human chronic neurodegenerative diseases contain ubiquitylated proteins. There could be several reasons for the accumulation of ubiquitylated proteins, including malfunction of the ubiquitin proteasome system (UPS). This hypothesis has been genetically tested in mice by conditional deletion of a proteasomal regulatory ATPase gene. The consequences of gene ablation in the forebrain include extensive neuronal death and the production of Lewy-like bodies containing ubiquitylated proteins as in dementia with Lewy bodies. Gene deletion in catecholaminergic neurons, including in the substantia nigra, recapitulates the neuropathology of Parkinson's disease. (C) 2008 Elsevier B.V. All rights reserved.

【 授权许可】

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