Abstract
Molecular chaperones are involved in a wide range of cellular events, such as protein folding and oligomeric protein complex assembly. DnaK- and DnaJ-like proteins are the two major classes of molecular chaperones in mammals. Recent studies have shown that DnaJ-like family proteins can inhibit polyglutamine aggregation, a hallmark of many neurodegenerative diseases, including Huntington's disease (HD). Although most DnaJ-like proteins studied are ubiquitously expressed, some have restricted expression, so it is possible that some specific chaperones may affect polyglutamine aggregation in specific neurons. In this report, we describe the isolation of a DnaJ-like protein MRJ and the characterization of its chaperone activity. Tissue distribution studies showed that MRJ is highly enriched in the central nervous system. In an in vitro cell model of HD, overexpressed MRJ effectively suppressed polyglutamine-dependent protein aggregation, caspase activity, and cellular toxicity. Collectively, these results suggest that MRJ has a relevant functional role in neurons.
Highlights
Molecular chaperones were initially identified by their appearance under conditions of stress
In Huntington’s disease (HD) cell models, overexpressed MRJ effectively suppressed the protein aggregation, caspase activity, and cellular toxicity induced by the mutant huntingtin, suggesting that MRJ may be a chaperone that acts on neuronal disease proteins
Using human embryonic kidney 293 cells transfected with mutant huntingtin N terminus as a model, we found that cells transfected with huntingtin alone exhibited puncta or aggregates distributed throughout the cytoplasm and nucleus (Fig. 4A)
Summary
Heat-shock protein 70; HD, Huntington’s disease; RACE, rapid amplification of cDNA ends; GST, glutathione S-transferase; ORF, open reading frame; UTR, untranslated repeat; MTS, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1propanesulfonic acid; PIPES, 1,4-piperazinediethanesulfonic acid; SCA1, spinocerebellar ataxia type 1. Chaperone MRJ Inhibits Huntingtin-induced Toxicity gregation [23], whereas Hsp40/HDJ-1 overexpression inhibited polyglutamine-induced aggregation [24, 25]. In HD cell models, overexpressed MRJ effectively suppressed the protein aggregation, caspase activity, and cellular toxicity induced by the mutant huntingtin, suggesting that MRJ may be a chaperone that acts on neuronal disease proteins
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