Protein aggregation stands at the center of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease (HD). HD is caused by a mutation in the huntingtin gene, resulting in expansion of poly-glutamine repeats, causing aggregation of the huntingtin protein in the cell. One of the consequences of this aggregation is endoplasmic reticulum (ER) stress, which interferes with cell function and eventually leads to cell death, predominantly in the brain striatum. In recent years, a key pathway of the unfolded protein response (UPR)- the PERK pathway, has been targeted as a possible therapeutic approach for neurodegenerative diseases. Previous research in neurodegenerative diseases showed positive effects of PERK inhibition, suggesting that decreasing phosphorylation of its substrate, eIF2α, interferes with the initiation of the apoptotic pathway upon long term ER stress. However, other studies suggested that, paradoxically, the opposite strategy, increasing eIF2α phosphorylation by PERK activation or by inhibition of the phosphatase subunit GADD34, is also beneficial for cell survival. Higher levels of eIF2α-P lead to inhibition of protein translation, and as a result, reduce accumulation of damaged proteins in the cell. In our recent work, treatment with a PERK activator developed in our lab – MK-28, was attempted on cellular HD models and on the R6/2 transgenic mouse HD model. Cells in culture expressing polyglutamine-expanded huntingtin showed significantly increased survival, upon ER stress. MK-28 treated mice showed significant improvement in their motor performance and physiologic measurements, suggesting that PERK activation postponed the appearance of HD symptoms. These findings suggest a new possible therapy for HD, and possibly open a new approach for treatment of other neurodegenerative diseases.