Nature Genetics37, 771 - 776 (2005)
Published online: 26 June 2005; | doi:10.1038/ng1591
Dynein mutations impair autophagic clearance of aggregate-prone proteins
Brinda Ravikumar1, 4, Abraham Acevedo-Arozena2, 4, Sara Imarisio1, 3, Zdenek Berger1, 3, Coralie Vacher1, Cahir J O'Kane3, Steve D M Brown2
& David C Rubinsztein1
1
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK.
2
Medical Research Council Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
3
Department of Genetics, University of Cambridge, CB2 3EH, UK.
Mutations that affect the dynein motor machinery are sufficient to cause motor neuron disease. It is not known why there are aggregates or inclusions in affected tissues in mice with such mutations and in most forms of human motor neuron disease. Here we identify a new mechanism of inclusion formation by showing that decreased dynein function impairs autophagic clearance of aggregate-prone proteins. We show that mutations of the dynein machinery enhanced the toxicity of the mutation that causes Huntington disease in fly and mouse models. Furthermore, loss of dynein function resulted in premature aggregate formation by mutant huntingtin and increased levels of the autophagosome marker LC3-II in both cell culture and mouse models, compatible with impaired autophagosome-lysosome fusion.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
