Dynein mutations impair autophagic clearance of aggregate-prone proteins.

Abstract	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.
Authors	Brinda Ravikumar, Abraham Acevedo-Arozena, Sara Imarisio, Zdenek Berger, Coralie Vacher, Cahir J O'Kane, Steve D M Brown, David C Rubinsztein
Journal	Nature genetics (Nat Genet) Vol. 37 Issue 7 Pg. 771-6 (Jul 2005) ISSN: 1061-4036 [Print] United States
PMID	15980862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	HTT protein, human Htt protein, mouse Htt protein, rat Huntingtin Protein Nerve Tissue Proteins Nuclear Proteins Synucleins Adenylyl Imidodiphosphate 9-(2-hydroxy-3-nonyl)adenine Proteasome Endopeptidase Complex Dyneins Adenine
Topics	Adenine (analogs & derivatives, pharmacology) Adenylyl Imidodiphosphate (pharmacology) Animals Autophagy Behavior, Animal Brain (pathology) COS Cells Chlorocebus aethiops Crosses, Genetic Diptera Dyneins (antagonists & inhibitors, genetics, metabolism) Humans Huntingtin Protein Huntington Disease (genetics, metabolism, pathology) Inclusion Bodies (metabolism) Mice Mice, Mutant Strains Mutation Nerve Tissue Proteins (genetics, metabolism) Nuclear Proteins (genetics) PC12 Cells Proteasome Endopeptidase Complex (metabolism) Rats Synucleins

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