Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/44007
Title: Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase
Author: Mashimo,T.
Hadjebi, Ouadah
Amair-Pinedo, Fabiola
Tsurumi,T.
Langa, Francina
Serikawa,T.
Sotelo,C.
Guénet, Jean-Louis
Rosa López, José Luis
Keywords: Neurones
Genètica molecular
Regulació cel·lular
Proteïnes de membrana
Neurons
Molecular genetics
Cellular control mechanisms
Membrane proteins
Issue Date: 24-Dec-2009
Publisher: Public Library of Science (PLoS)
Abstract: The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domain shave been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a GuA transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N- terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.
Note: Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1000784
It is part of: PLoS Genetics, 2009, vol. 5, num. 12, p. e1000784
Related resource: http://dx.doi.org/10.1371/journal.pgen.1000784
URI: http://hdl.handle.net/2445/44007
ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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