A role of cellular translation regulation associated with toxic Huntingtin protein
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.
KeywordsHuntington’s disease Functional-prion-like protein Translation regulator Orb2
We acknowledge Prof. Troy Littleton, Prof. Kausik Si for sharing several Drosophila stocks and plasmids with us. We also thank Addgene and Bloomington Drosophila stock center for some of the plasmids and fly lines used in this work. We thank Prof. Kausik Si, Dr. Gunther Hollopeter, Dr. Irina Dudanova and Dr. Deepa Subramanyam for their suggestions on the work. We thank Dr. Vidisha Tripathi for letting us use the qPCR machine. A.M acknowledges Dr. Arvind Sahu, Dr. Vasudevan Seshadri and Dr. Ajay Pillai for their support. This work was supported by funding from Wellcome Trust-DBT India Alliance intermediate fellowship (IA/I/13/2/501030) to AM along with intramural funding from NCCS. TB was supported by Ramalingaswami fellowship from DBT (BT/RLF/Re-entry/54/2013) and IYBA Grant (BT/09/IYBA/2015/03).
HJ started this project and identified Orb2 isoforms as rescuers of Htt pathogenicity. VG performed the S2 cell polysome and puromycin incorporation experiments. MS1 performed S2 cell imaging and FRAP experiments. MS2 did the Yeast polysome experiments. AR did the Orb2 rescue and Orb2 RNAi experiments. MD performed the Orb2 level quantitation, OPP staining, Htt clonings, and immunoprecipitation experiments. RC and AD performed the Yeast lethality and growth curve experiments. TB and AM conceived and designed the experiments. AM wrote the manuscript.
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Conflict of interest
Authors declare no competing interests.
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