scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

• Published in: The Journal of biological chemistry 2014-02, Vol.289 (6), p.3666-3676
• Main Authors: Lai, Aaron Y., Lan, Cynthia P., Hasan, Salwa, Brown, Mary E., McLaurin, JoAnne
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; Autophagy; huntingtin; Huntingtin Protein; Huntington Disease; Inositol - pharmacology; Lysosomes; Lysosomes - genetics; Lysosomes - metabolism; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurodegenerative Diseases; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PC12 Cells; Peptides - genetics; Peptides - metabolism; Proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteolysis - drug effects; Rats; scyllo-Inositol
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.501635

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. Background: Effects of scyllo-inositol, a modulator of misfolded protein accumulation, were tested in a cellular model of Huntington disease. Results:scyllo-Inositol lowered mutant huntingtin aggregation and decreased protein abundance through proteasomal and lysosomal degradation. Conclusion:scyllo-Inositol promotes mutant huntingtin degradation in a model of Huntington disease. Significance: In contrast to other compounds targeting mutant huntingtin aggregation and accumulation, scyllo-inositol promotes effective degradation.