Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane
Disease Models & Mechanisms
The Company of Biologists
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Brandstaetter, H., Kruppa, A., & Buss, F. (2014). Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane. Disease Models & Mechanisms, 7 1335-1340. https://doi.org/10.1242/dmm.017368
Huntingtin is a large membrane associated scaffolding protein that associates with endocytic and exocytic vesicles and modulates their trafficking along cytoskeletal tracks. Although Huntington's disease progression is linked to toxic accumulation of mutant huntingtin protein, loss of wildtype huntingtin function may 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 ER-to-Golgi transport and a reduction in the number of cargo vesicles leaving the trans-Golgi network. In addition, 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 Q140 huntingtin knock-in mice that lack wildtype huntingtin expression. Interestingly, heterozygous fibroblasts from a Huntington’s disease patient with a Q180 expansion displayed no obvious defects in the early secretory pathway. Thus, our results highlight the requirement for wildtype huntingtin at distinct steps along the secretory pathway.
Exocytosis, huntingtin, ER, Golgi, vesicle fusion
This work was supported by the Cure Huntingtin’s Disease Initiative (CHDI) (H.B. and A.J.K.), the Wellcome Trust (grant number 086743 to F.B.) and the Medical Research Council (grant number MR/K000888/1 to F.B). The CIMR is in receipt of a strategic award from the Wellcome Trust (grant number 100140).
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (086743/Z/08/Z)
External DOI: https://doi.org/10.1242/dmm.017368
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246722
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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