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

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 β-amyloid (Aβ) is the main neuropathological feature. It is now bel...

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Bibliographic Details
Published in:Neurobiology of aging 2002-09, Vol.23 (5), p.957-976
Main Authors: Forloni, Gianluigi, Terreni, Liana, Bertani, Ilaria, Fogliarino, Sergio, Invernizzi, Roberto, Assini, Andrea, Ribizzi, Giuseppe, Negro, Alessandro, Calabrese, Elena, Volonté, Maria Antonietta, Mariani, Claudio, Franceschi, Massimo, Tabaton, Massimo, Bertoli, Alessandro
Format: Article
Language:English
Subjects:
Aged
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Amyloid
Amyloid - chemistry
Amyloid - metabolism
Biological and medical sciences
Cysteine Endopeptidases - metabolism
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Humans
Ligases - metabolism
Medical sciences
Membrane Proteins - chemistry
Membrane Proteins - metabolism
Multienzyme Complexes - metabolism
Nerve Tissue Proteins - metabolism
Neurology
Parkin ubiquitin–proteasome system (UPS)
Parkinson Disease - genetics
Parkinson Disease - metabolism
Presenilin-1
Presenilin-2
Presenilins
Proteasome Endopeptidase Complex
Protein Folding
Synuclein
Synucleins
Ubiquitin - metabolism
Ubiquitin-Protein Ligases
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Description
Summary: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 β-amyloid (Aβ) 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 (PS1) 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.
ISSN:0197-4580
1558-1497
DOI:10.1016/S0197-4580(02)00076-3