Journal
EXPERIMENTAL NEUROLOGY
Volume 179, Issue 1, Pages 38-46Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/exnr.2002.8050
Keywords
Parkinson's disease (PD); ubiquitin-proteasome system; alpha-synuclein; PA700; PA28; aggresome; substantia nigra pars compacta (SNc); Lewy body inclusion
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS033772, R01NS041263, P50NS039793] Funding Source: NIH RePORTER
- NINDS NIH HHS [P50 NS039793-04S1, R01 NS041263-03, P50 NS 39793, NS 33772, NS 41263] Funding Source: Medline
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Parkinson's disease (PD) is characterized pathologically by preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). Nigral cell death is accompanied by the accumulation of a wide range of poorly degraded proteins and the formation of proteinaceous inclusions (Lewy bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin G terminal hydrolase L1, are associated with neurodegeneration in some familial forms of PD. We now show that, in comparison to age-matched controls, alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the SNc in sporadic PD. In addition, while the levels of the PA700 proteasome activator are reduced in the SNe in PD, PA700 expression is increased in other brain regions such as the frontal cortex and striatum. We also found that levels of the PA28 proteasome activator are very low to almost undetectable in the SNc compared to other brain areas in both normal and PD subjects. These findings suggest that failure of the ubiquitin-proteasome system to adequately clear unwanted proteins may underlie vulnerability and degeneration of the SNc in both sporadic and familial PD. (C) 2002 Elsevier Science (USA).
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