title: Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease.
abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein (htt) that mediates formation of intracellular protein aggregates. In the brains of HD patients and HD transgenic mice, accumulation of protein aggregates has been causally linked to lesions in axo-dendritic and synaptic compartments. Here we show that dendritic spines - sites of synaptogenesis - are lost in the proximity of htt aggregates because of functional defects in local endosomal recycling mediated by the Rab11 protein. Impaired exit from recycling endosomes (RE) and association of endocytosed protein with intracellular structures containing htt aggregates was demonstrated in cultured hippocampal neurons cells expressing a mutant htt fragment. Dendrites in hippocampal neurons became dystrophic around enlarged amphisome-like structures positive for Rab11, LC3 and mutant htt aggregates. Furthermore, Rab11 overexpression rescues neurodegeneration and dramatically extends lifespan in a Drosophila model of HD. Our findings are consistent with the model that mutant htt aggregation increases local autophagic activity, thereby sequestering Rab11 and diverting spine-forming cargo from RE into enlarged amphisomes. This mechanism may contribute to the toxicity caused by protein misfolding found in a number of neurodegenerative diseases.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Richards
authors.forename: C
authors.initials: C
authors.lastname: Didszun
authors.forename: S
authors.initials: S
authors.lastname: Campesan
authors.forename: A
authors.initials: A
authors.lastname: Simpson
authors.forename: B
authors.initials: B
authors.lastname: Horley
authors.forename: K W
authors.initials: KW
authors.lastname: Young
authors.forename: P
authors.initials: P
authors.lastname: Glynn
authors.forename: K
authors.initials: K
authors.lastname: Cain
authors.forename: C P
authors.initials: CP
authors.lastname: Kyriacou
authors.forename: F
authors.initials: F
authors.lastname: Giorgini
authors.forename: P
authors.initials: P
authors.lastname: Nicotera
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure*; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C506812:Htt protein, mouse; C499524:Htt protein, rat