Protein misfolding in Alzheimer's and Parkinson's disease:: genetics and molecular mechanisms

被引:110
作者
Forloni, G
Terreni, L
Bertani, I
Fogliarino, S
Invernizzi, R
Assini, A
Ribizzi, G
Negro, A
Calabrese, E
Volonté, MA
Mariani, C
Franceschi, M
Tabaton, M
Bertoli, A
机构
[1] Ist Ric Farmacol Mario Negri, Dept Neurosci, I-20157 Milan, Italy
[2] Univ Genoa, Dept Neourol Sci, Milan, Italy
[3] Univ Padua, Dept Biol Chem, Milan, Italy
[4] IRCCS S Maria Nascente, Milan, Italy
[5] IRCCS San Raffaele, Dept Neurol, Milan, Italy
[6] Osped L Sacco, Dept Neurol, Milan, Italy
[7] Clin S Maria HSR, Castellanza, Va, Italy
关键词
presenilins; amyloid; synuclein; Parkin ubiquitin-proteasome system (UPS);
D O I
10.1016/S0197-4580(02)00076-3
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
The accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. A causal role of protein aggregation was originally proposed in Alzheimer's disease (AD) where extracellular deposition of beta-amyloid (Abeta) is the main neuropathological feature. It is now believed that intracellular deposition of aggregated proteins may be relevant in Parkinson's disease (PD), amyotrophic lateral sclerosis and polyglutamine disorders. An impairment of ubiquitin-proteasome system (UPS) appears directly involved in these disorders. We reviewed the results on the role of protein misfolding in AD and PD and the influence of mutations associated with these diseases on the expression of amyloidogenic proteins. Results of genetic screening of familial cases of AD and PD are summarized. In the familial AD population (70 subjects) we found several mutations of the presenilin 1 (PS 1) gene with a frequency of 12.8% and one mutation in the gene encoding the protein precursor of amyloid (APP) (1.4%). One mutation of Parkin in the homozygous form and two in the heterozygous form were identified in our PD population. We also reported data obtained with synthetic peptides and other experimental models, for evaluation of the pathogenic role of mutations in terms of protein misfolding. (C) 2002 Elsevier Science Inc. All rights reserved.
引用
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页码:957 / 976
页数:20
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