Joag, H., Ghatpande, V., Desai, M., Sarkar, M., Raina, A., Shinde, M., Chitale, R., Deo, A., Bose, T., Majumdar, A. (2020). A role of cellular translation regulation associated with toxic Huntingtin protein.  Cell. Molec. Life Sci. 77(18): 3657--3670.

FBrf0246759

Research paper

Huntington's disease (HD) is a severe neurodegenerative disorder caused by poly Q repeat expansion in the Huntingtin (Htt) gene. While the Htt amyloid aggregates are known to affect many cellular processes, their role in translation has not been addressed. Here we report that pathogenic Htt expression causes a protein synthesis deficit in cells. We find a functional prion-like protein, the translation regulator Orb2, to be sequestered by Htt aggregates in cells. Co-expression of Orb2 can partially rescue the lethality associated with poly Q expanded Htt. These findings can be relevant for HD as human homologs of Orb2 are also sequestered by pathogenic Htt aggregates. Our work suggests that translation dysfunction is one of the contributors to the pathogenesis of HD and new therapies targeting protein synthesis pathways might help to alleviate disease symptoms.

PMC11105026 (PMC) (EuropePMC)