title: Protein misfolding in Alzheimer's and Parkinson's disease: genetics and molecular mechanisms.
abstract: 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 (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.
authors.affiliation: Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. forloni@marionegri.it
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Liana
authors.initials: L
authors.lastname: Terreni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bertani
authors.forename: Sergio
authors.initials: S
authors.lastname: Fogliarino
authors.forename: Roberto
authors.initials: R
authors.lastname: Invernizzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Assini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ribizzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Negro
authors.forename: Elena
authors.initials: E
authors.lastname: Calabrese
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Volonté
authors.forename: Claudio
authors.initials: C
authors.lastname: Mariani
authors.forename: Massimo
authors.initials: M
authors.lastname: Franceschi
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertoli
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D008025:Ligases / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding; D051843:Synucleins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D000682:Amyloid; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051843:Synucleins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases