Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation.

Autor: El-Daher MT; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France., Hangen E; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France., Bruyère J; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Inserm U836, Grenoble, France Grenoble Institut des Neurosciences, GIN University of Grenoble Alpes, Grenoble, France., Poizat G; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France., Al-Ramahi I; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Pardo R; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France., Bourg N; ISMO, CNRS UMR8214 University of Paris Sud, Orsay, France CPBM FR2764 University of Paris Sud, Orsay, France., Souquere S; CNRS UMR8122, Villejuif, France Institut Gustave Roussy, Villejuif, France., Mayet C; ISMO, CNRS UMR8214 University of Paris Sud, Orsay, France CPBM FR2764 University of Paris Sud, Orsay, France., Pierron G; CNRS UMR8122, Villejuif, France Institut Gustave Roussy, Villejuif, France., Lévêque-Fort S; ISMO, CNRS UMR8214 University of Paris Sud, Orsay, France CPBM FR2764 University of Paris Sud, Orsay, France., Botas J; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Humbert S; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Inserm U836, Grenoble, France Grenoble Institut des Neurosciences, GIN University of Grenoble Alpes, Grenoble, France sandrine.humbert@inserm.fr frederic.saudou@inserm.fr., Saudou F; Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Inserm U836, Grenoble, France Grenoble Institut des Neurosciences, GIN University of Grenoble Alpes, Grenoble, France CHU de Grenoble, Grenoble, France sandrine.humbert@inserm.fr frederic.saudou@inserm.fr.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2015 Sep 02; Vol. 34 (17), pp. 2255-71. Date of Electronic Publication: 2015 Jul 12.
DOI: 10.15252/embj.201490808
Abstrakt: Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease.
(© 2015 The Authors.)
Databáze: MEDLINE
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