Huntington disease (HD) is associated with progressive degeneration of the striatum, but the cause of this cell death is unclear. Leitman and colleagues examined cultures of normal murine striatal cells, and similar cells that expressed the polyglutamine-expanded form of the huntingtin protein. Striatal cells were found to be particularly sensitive to chemicals that cause endoplasmic reticulum stress, and presence of the pathogenic huntingtin protein exacerbated this sensitivity. Huntingtin-expressing striatal neurons had higher levels of the protein phosphorylation factor eIF2α than did the normal cells. Administration of an eIF2α kinase inhibitor reduced neurotoxicity, and might, therefore, represent a target for future drug therapies for HD.
References
Leitman, J. et al. ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin. PLoS ONE 9, e90803 (2014)
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Possible cellular mechanism for striatal degeneration in Huntington disease. Nat Rev Neurol 10, 182 (2014). https://doi.org/10.1038/nrneurol.2014.56
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DOI: https://doi.org/10.1038/nrneurol.2014.56