title: α-Synuclein accumulates in huntingtin inclusions but forms independent filaments and its deficiency attenuates early phenotype in a mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is the most common of nine inherited neurological disorders caused by expanded polyglutamine (polyQ) sequences which confer propensity to self-aggregate and toxicity to their corresponding mutant proteins. It has been postulated that polyQ expression compromises the folding capacity of the cell which might affect other misfolding-prone proteins. α-Synuclein (α-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies. Point mutations in α-syn that favor self-aggregation or α-syn gene duplications lead to familial PD, thus indicating that increased α-syn aggregation or levels are sufficient to induce neurodegeneration. Since polyQ inclusions in HD and other polyQ disorders are immunopositive for α-syn, we speculated that α-syn might be recruited as an additional mediator of polyQ toxicity. Here, we confirm in HD postmortem brains and in the R6/1 mouse model of HD the accumulation of α-syn in polyQ inclusions. By isolating the characteristic filaments formed by aggregation-prone proteins, we found that N-terminal mutant huntingtin (N-mutHtt) and α-syn form independent filamentous microaggregates in R6/1 mouse brain as well as in the inducible HD94 mouse model and that N-mutHtt expression increases the load of α-syn filaments. Accordingly, α-syn knockout results in a diminished number of N-mutHtt inclusions in transfected neurons and also in vivo in the brain of HD mice. Finally, α-syn knockout attenuates body weight loss and early motor phenotype of HD mice. This study therefore demonstrates that α-syn is a modifier of polyQ toxicity in vivo and raises the possibility that potential PD-related therapies aimed to counteract α-syn toxicity might help to slow HD.
authors: Center for Molecular Biology Severo Ochoa, CSIC/UAM, Madrid, Spain.
authors: Cristina
authors: C
authors: Tomás-Zapico
authors: María
authors: M
authors: Díez-Zaera
authors: Isidre
authors: I
authors: Ferrer
authors: Pilar
authors: P
authors: Gómez-Ramos
authors: María A
authors: MA
authors: Morán
authors: M Teresa
authors: MT
authors: Miras-Portugal
authors: Miguel
authors: M
authors: Díaz-Hernández
authors: José J
authors: JJ
authors: Lucas
mesh_terms: D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology* / Q000473:pathology; D002479:Inclusion Bodies / Q000737:chemistry*; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009154:Mutation; D017072:Neostriatum / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics; D009474:Neurons / Q000737:chemistry; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D015431:Weight Loss; D051844:alpha-Synuclein / Q000032:analysis* / Q000235:genetics
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein