ReviewEndoplasmic reticulum stress: The cause and solution to Huntington's disease?

- Endoplasmic reticulum (ER) stress is linked to HD.
- Activation of the unfolded protein response (UPR) is a hallmark of HD.
- UPR activation can be both protective and detrimental for cells.
- ER stress is a target for development of new therapeutic approaches for HD.

Accumulation of misfolded proteins is a hallmark of many human diseases, including several incurable neurological disorders, such as Huntington's disease (HD). In HD, expansion of a polyglutamine stretch within the first exon of the Huntingtin protein (Htt) leads to Htt misfolding, aberrant protein aggregation, and progressive appearance of disease symptoms. Several studies in various organisms (from yeast to humans) have identified the accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER stress) as a crucial determinant of cellular toxicity in HD. In this review, we highlight the recent research linking HD to ER stress. We also discuss how the modulation of signaling pathways responsible for coping with misfolded protein accumulation in the ER may constitute attractive methods to reduce toxicity and identify new therapeutic targets for treatment of HD.This article is part of a Special Issue entitled SI:ER stress.