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Titolo:
Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity
Autore:
Ellerby, LM; Andrusiak, RL; Wellington, CL; Hackam, AS; Propp, SS; Wood, JD; Sharp, AH; Margolis, RL; Ross, CA; Salvesen, GS; Hayden, MR; Bredesen, DE;
Indirizzi:
Burnham Inst, Program Aging, La Jolla, CA 92037 USA Burnham Inst La JollaCA USA 92037 Program Aging, La Jolla, CA 92037 USA Burnham Inst, Program Apoptosis, La Jolla, CA 92037 USA Burnham Inst La Jolla CA USA 92037 gram Apoptosis, La Jolla, CA 92037 USA UnivBCritish Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver,Univ British Columbia Vancouver BC Canada V52 4H4 & Therapeut, Vancouver, Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 ychiat, Baltimore, MD 21205 USA Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA Univ Calif San Diego San Diego CA USA 92093 osci, San Diego, CA 92093 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 13, volume: 274, anno: 1999,
pagine: 8730 - 8736
SICI:
0021-9258(19990326)274:13<8730:COAACS>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
REPEAT NEURODEGENERATIVE DISEASES; NEURONAL INTRANUCLEAR INCLUSIONS; CAG REPEAT; POLYGLUTAMINE TRACT; GLUTAMINE REPEATS; DRPLA PROTEIN; GENE; HUNTINGTIN; EXPANSION; APOPTOSIS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Bredesen, DE BurnhamAInst, Program Aging, 10901 N Torrey Pines Rd, La Jolla, CA 92037 US Burnham Inst 10901 N Torrey Pines Rd La Jolla CA USA 92037 US
Citazione:
L.M. Ellerby et al., "Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity", J BIOL CHEM, 274(13), 1999, pp. 8730-8736

Abstract

Dentatorubropallidoluysian atrophy (DRPLA) is one of eight autosomal dominant neurodegenerative disorders characterized by an abnormal CAG repeat expansion which results in the expression of a protein with a polyglutamine stretch of excessive length. We have reported recently that four of the gene products (huntingtin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) associated with these open reading frame triplet repeat expansions are substrates for the cysteine protease cell death executioners, the caspases, This led us to hypothesize that caspase cleavage of these proteins may represent a common step in the pathogenesis of each of these four neurodegenerative diseases. Here we present evidence that caspase cleavage of atrophin-1 modulates cytotoxicity and aggregate formation. Cleavage of atrophin-1 at Asp(109) by caspases is critical for cytotoxicity because a mutant atrophin-1 that is resistant to caspase cleavage is associated with significantly decreased toxicity. Further, the altered cellular localization within the nucleus and aggregate formation associated with the expanded form of atrophin-1 are completely suppressed by mutation of the caspase cleavage site at Asp(109). These results provide support for the toxic fragment hypothesis whereby cleavage of atrophin-1 by caspases may be an important step in the pathogenesis of DRPLA. Therefore, inhibiting caspase cleavage of the polyglutamine-containing proteins may be a feasible therapeutic strategy to prevent cell death.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/03/20 alle ore 22:37:45