Regulation of by IRE1 prevents the accumulation of Huntingtin protein aggregates.

Huntington's disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression of exon 1 of mHTT in mouse cultured cells activates IRE1, the transmembrane sensor of stress in the endoplasmic reticulum, leading to degradation of the mRNA and repositioning of lysosomes and late endosomes toward the microtubule organizing center. Overriding degradation results in excessive accumulation of mHTT aggregates in both cultured cells and primary neurons.