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scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

Aaron Y Lai, Cynthia P Lan, Salwa Hasan, Mary E Brown, Joanne McLaurin

J Biol Chem. 2014 Feb 7;289(6):3666-76.

PMID: 24352657

Abstract:

Huntington disease is characterized by neuronal aggregates and inclusions containing polyglutamine-expanded huntingtin protein and peptide fragments (polyQ-Htt). We have used an established cell-based assay employing a PC12 cell line overexpressing truncated exon 1 of Htt with a 103-residue polyQ expansion that yields polyQ-Htt aggregates to investigate the fate of polyQ-Htt-drug complexes. scyllo-Inositol is an endogenous inositol stereoisomer known to inhibit accumulation and toxicity of the amyloid-β peptide and α-synuclein. In light of these properties, we investigated the effect of scyllo-inositol on polyQ-Htt accumulation. We show that scyllo-inositol lowered the number of visible polyQ-Htt aggregates and robustly decreased polyQ-Htt protein abundance without concomitant cellular toxicity. We found that scyllo-inositol-induced polyQ-Htt reduction was by rescue of degradation pathways mediated by the lysosome and by the proteasome but not autophagosomes. The rescue of degradation pathways was not a direct result of scyllo-inositol on the lysosome or proteasome but due to scyllo-inositol-induced reduction in mutant polyQ-Htt protein levels.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP488595	scyllo-Inositol		488-59-5	Price

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