Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease.
Huntington disease (HD) is caused by a polyglutamine-expansion mutation in huntingtin (HTT) that makes the protein toxic and aggregate-prone. The subcellular localisation of huntingtin and many of its interactors suggest a role in endocytosis, and recently it has been shown that huntingtin interacts indirectly with the early endosomal protein Rab5 through HAP40. Here we show that Rab5 inhibition enhanced polyglutamine toxicity, whereas Rab5 overexpression attenuated toxicity in our cell and fly models of HD. We tried to identify a mechanism for the Rab5 effects in our HD model systems, and our data suggest that Rab5 acts at an early stage of autophagosome formation in a macromolecular complex that contains beclin 1 (BECN1) and Vps34. Interestingly chemical or genetic inhibition of endocytosis also impeded macroautophagy, and enhanced aggregation and toxicity of mutant huntingtin. However, in contrast to Rab5, inhibition of endocytosis by various means suppressed autophagosome-lysosome fusion (the final step in the macroautophagy pathway) similar to bafilomycin A1. Thus, Rab5, which has previously been thought to be exclusively involved in endocytosis, has a new role in macroautophagy. We have previously shown that macroautophagy is an important clearance route for several aggregate-prone proteins including mutant huntingtin. Thus, better understanding of Rab5-regulated autophagy might lead to rational therapeutic targets for HD and other protein-conformation diseases.
Ravikumar
Brinda
B
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
Imarisio
Sara
S
Sarkar
Sovan
S
O'Kane
Cahir J
CJ
Rubinsztein
David C
DC
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004330:Drosophila; D006367:HeLa Cells; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D014162:Transfection; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D020696:rab5 GTP-Binding Proteins