Abstract
Huntingtin is a large membrane-associated scaffolding protein that associates with endocytic and exocytic vesicles and modulates their trafficking along cytoskeletal tracks. Although the progression of Huntington’s disease is linked to toxic accumulation of mutant huntingtin protein, loss of wild-type huntingtin function might also contribute to neuronal cell death, but its precise function is not well understood. Therefore, we investigated the molecular role of huntingtin in exocytosis and observed that huntingtin knockdown in HeLa cells causes a delay in endoplasmic reticulum (ER)-to-Golgi transport and a reduction in the number of cargo vesicles leaving the trans-Golgi network. In addition, we found that huntingtin is required for secretory vesicle fusion at the plasma membrane. Similar defects in the early exocytic pathway were observed in primary fibroblasts from homozygous Htt140Q/140Q knock-in mice, which have the expansion inserted into the mouse huntingtin gene so lack wild-type huntingtin expression. Interestingly, heterozygous fibroblasts from a Huntington’s disease patient with a 180Q expansion displayed no obvious defects in the early secretory pathway. Thus, our results highlight the requirement for wild-type huntingtin at distinct steps along the secretory pathway.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that is caused by a polyglutamine repeat expansion at the N-terminus of the protein huntingtin (HTT) (DiFiglia et al, 1997; Imarisio et al, 2008)
HD is linked to mutations in the HTT gene that lead to an extended polyglutamine repeat at the N-terminus of the huntingtin protein
To investigate the role of wild-type huntingtin in protein secretion, the authors use a combination of tissue culture cell lines, including primary fibroblasts isolated from homozygous Htt140Q/140Q knock-in mice, HTTknockdown human HeLa cells and primary fibroblasts obtained from a heterozygous individual with HD (HTT+/180Q)
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that is caused by a polyglutamine (polyQ) repeat expansion at the N-terminus of the protein huntingtin (HTT) (DiFiglia et al, 1997; Imarisio et al, 2008). The age of disease onset and the rate of aggregation depend on the length of the polyQ expansion; for example, 40-50 repeats cause adult-onset HD, whereas a large number of repeats (e.g. 180) leads to juvenile forms of the disease (Squitieri et al, 2002; Snell et al, 1993). A detailed analysis of the diverse cellular functions of wild-type huntingtin is required to understand the exact contribution(s) that loss of wild-type huntingtin plays in disease progression (Schulte and Littleton, 2011; Caviston and Holzbaur, 2009). Huntingtin is a large scaffold protein that associates with a variety of cellular binding partners (Shirasaki et al, 2012), which mediate huntingtin’s multiple roles in intracellular transport and membrane trafficking (Caviston and Holzbaur, 2009). Huntingtin can associate through optineurin with the actin-based motor myosin VI, and huntingtin is in the unique position to coordinate transport along the microtubule and actin cytoskeleton (Hattula and Peränen, 2000; Sahlender et al, 2005)
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