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Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington's disease.

Authors: Pal, Arun  Severin, Fedor  Lommer, Barbara  Shevchenko, Anna  Zerial, Marino 
Citation: Pal A, etal., J Cell Biol. 2006 Feb 13;172(4):605-18. doi: 10.1083/jcb.200509091.
Pubmed: (View Article at PubMed) PMID:16476778
DOI: Full-text: DOI:10.1083/jcb.200509091

The molecular mechanisms underlying the targeting of Huntingtin (Htt) to endosomes and its multifaceted role in endocytosis are poorly understood. In this study, we have identified Htt-associated protein 40 (HAP40) as a novel effector of the small guanosine triphosphatase Rab5, a key regulator of endocytosis. HAP40 mediates the recruitment of Htt by Rab5 onto early endosomes. HAP40 overexpression caused a drastic reduction of early endosomal motility through their displacement from microtubules and preferential association with actin filaments. Remarkably, endogenous HAP40 was up-regulated in fibroblasts and brain tissue from human patients affected by Huntington's disease (HD) as well as in STHdhQ(111) striatal cells established from a HD mouse model. These cells consistently displayed altered endosome motility and endocytic activity, which was restored by the ablation of HAP40. In revealing an unexpected link between Rab5, HAP40, and Htt, we uncovered a new mechanism regulating cytoskeleton-dependent endosome dynamics and its dysfunction under pathological conditions.


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CRRD Object Information
CRRD ID: 14697710
Created: 2019-08-03
Species: All species
Last Modified: 2019-08-03
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.