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Titolo:
Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis
Autore:
Tanaka, Y; Engelender, S; Igarashi, S; Rao, RK; Wanner, T; Tanzi, RE; Sawa, A; Dawson, VL; Dawson, TM; Ross, CA;
Indirizzi:
Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 ychiat, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 urosci, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 Neurol, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 hysiol, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 ol Med, Baltimore, MD 21205 USA Fed Univ Rio De Janeiro, Dept Anat, BR-21941 Rio De Janeiro, Brazil Fed Univ Rio De Janeiro Rio De Janeiro Brazil BR-21941 e Janeiro, Brazil Harvard Univ, MIT, Sch Med, Dept Neurol, Charlestown, MA 02129 USA HarvardUniv Charlestown MA USA 02129 t Neurol, Charlestown, MA 02129 USA
Titolo Testata:
HUMAN MOLECULAR GENETICS
fascicolo: 9, volume: 10, anno: 2001,
pagine: 919 - 926
SICI:
0964-6906(20010415)10:9<919:IEOMAD>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
UBIQUITIN-PROTEIN LIGASE; INDUCED CELL-DEATH; PARKINSONS-DISEASE; LEWY BODIES; PERMEABILITY TRANSITION; OXIDATIVE STRESS; NEURONAL DEATH; CYTOCHROME-C; MICE; PATHOGENESIS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Ross, CA Johns Hopkins Univ, Sch Med, Dept Psychiat, 720 Rutland Ave,Ross Res Bldg,Room 618, Baltimore, MD 21205 USA Johns Hopkins Univ 720 Rutland Ave,Ross Res Bldg,Room 618 Baltimore MD USA 21205
Citazione:
Y. Tanaka et al., "Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis", HUM MOL GEN, 10(9), 2001, pp. 919-926

Abstract

Parkinson's disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra, Although mutations in alpha -synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD, We established inducible PC12 cell lines in which wild-type or mutant alpha -synuclein can be de-repressed by removing doxycycline, Differentiated PC12 cell lines expressing mutant alpha -synuclein showed decreased activity of proteasomes without direct toxicity, Cells expressing mutant alpha -synucleinshowed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A, These data suggest that expression of mutant alpha -synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 06:39:18