Helping neurons cope with ER stress in Huntington’s disease

Progressive decay of protein quality control machineries compromises protein homeostasis and leads to endoplasmic reticulum (ER) stress and its cytotoxic effects. This phenomenon underlies late onset neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease (HD). HD is caused by a mutation in the huntingtin gene, resulting in expansion of polyglutamine repeats, causing aggregation of the huntingtin protein. This aggregation causes a significant increase in ER stress, which interferes with cell function, leading to cell death, predominantly in the brain striatum. The PERK pathway of the unfolded protein response has recently been targeted as a possible therapeutic approach for neurodegenerative diseases. Increasing eIF2α phosphorylation by PERK activation or by inhibition of the phosphatase subunit GADD34 has positive effects. Higher levels of eIF2α-P inhibit protein translation, reducing accumulation of damaged proteins in the cell. Direct PERK activation has the advantage of not affecting long-term recovery of eIF2α function by dephosphorylation by GADD34. We have tested a potent PERK activator developed in our lab, MK-28, on cellular and mouse HD models. MK-28 increased significantly survival of a striatal cell line expressing polyglutamine-expanded huntingtin (STHdh^Q111/111). MK-28 - treated R6/2 HD model mice showed significant improvement in their motor performance, physiologic measurements and survival, suggesting that PERK activation postpones the appearance of HD symptoms. These findings suggest a new potential therapy for HD, and also likely for other neurodegenerative diseases.