Lu, Boxun and Palacino, James (2013) A novel human embryonic stem cell-derived Huntington's disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration. FASEB Journal. ISSN 0892-6638

Abstract

Most neurodegenerative diseases are linked to aberrant accumulation of aggregation-prone proteins. Among them, Huntington’s disease (HD) is caused by an expanded polyQ stretch in the N-terminus of the mutant huntingtin (mHTT) protein, which gets cleaved and aggregates in the brain. Recently established human induced pluripotent stem cell (hiPSC)-derived HD neurons exhibit some disease relevant phenotypes and provide tools for HD research. However, they have limitations such as genetic heterogeneity, an absence of mHTT aggregates, and lack a robust neurodegeneration phenotype. In addition, the relationship between the phenotype and mHTT protein levels has not been elucidated. Herein, we present a human embryonic stem cell (hESC)-derived HD neuronal model expressing HTTexon1 fragments which address the deficiencies enumerated above. The wild-type and HD lines are derived from an isogenic background, exhibit insoluble mHTT aggregates, and neurodegeneration. We also demonstrate a quantitative relationship between neurodegeneration and soluble monomeric (but not oligomeric or aggregated) mHTT levels. Reduction of ~10% of mHTT protein is sufficient to prevent toxicity, whereas ~90% reduction of wild-type HTT protein is safe and well tolerated in these cells. A known HD toxicity modifier (Rhes) showed expected rescue of neurodegeneration. Therefore, the hESC-derived neuronal models complement existing iPSC-derived neuronal models and provide valuable tools for HD research.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/8180