Proteasome inhibition causes nigral degeneration with inclusion bodies in rats

被引：221

作者：

McNaught, KS

Björklund, LM

Belizaire, R

Isacson, O

Jenner, P

Olanow, CW

机构：

[1] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA

[2] Harvard Univ, Sch Med, Neurogenerat Lab, Belmont, MA 02478 USA

[3] Kings Coll London, GKT Sch Biomed Sci, Neurodegenerat Dis Res Ctr, London SE1 1UL, England

来源：

NEUROREPORT | 2002年 / 13卷 / 11期

关键词：

lactacystin; Lewy body inclusion; parkin; Parkinson's disease; alpha-synuclein; ubiquitin-proteasome system; substantia nigra pars compacta;

D O I：

10.1097/00001756-200208070-00018

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Structural and functional defects in 26/20S proteasomes occur in the substantia nigra pars compacta and may underlie protein accumulation, Lewy body formation and dopaminergic neuronal death in Parkinson's disease. We therefore determined the pathogenicity of proteasomal impairment following stereotaxic unilateral infusion of lactacystin, a selective proteasome inhibitor, into the substantia nigra pars compacta of rats. These animals became progressively bradykinetic, adopted a stooped posture and displayed contralateral head tilting. Administration of apomorphine to lactacystin-treated rats reversed behavioral abnormalities and induced contralateral rotations. Lactacystin caused dose-dependent degeneration of dopaminergic cell bodies and processes with the cytoplasmic accumulation and aggregation of alpha-synuclein to form inclusion bodies. These findings support the notion that failure of the ubiquitin-proteasome system to degrade and clear unwanted proteins is an important etiopathogenic factor in Parkinson's disease.

引用

页码：1437 / 1441

页数：5

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