| First Author | Tomás-Zapico C | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 3 | Pages | 495-510 |
| PubMed ID | 22045698 | Mgi Jnum | J:179713 |
| Mgi Id | MGI:5302922 | Doi | 10.1093/hmg/ddr507 |
| Citation | Tomas-Zapico C, et al. (2012) alpha-Synuclein accumulates in huntingtin inclusions but forms independent filaments and its deficiency attenuates early phenotype in a mouse model of Huntington's disease. Hum Mol Genet 21(3):495-510 |
| abstractText | 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. alpha-Synuclein (alpha-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies. Point mutations in alpha-syn that favor self-aggregation or alpha-syn gene duplications lead to familial PD, thus indicating that increased alpha-syn aggregation or levels are sufficient to induce neurodegeneration. Since polyQ inclusions in HD and other polyQ disorders are immunopositive for alpha-syn, we speculated that alpha-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 alpha-syn in polyQ inclusions. By isolating the characteristic filaments formed by aggregation-prone proteins, we found that N-terminal mutant huntingtin (N-mutHtt) and alpha-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 alpha-syn filaments. Accordingly, alpha-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, alpha-syn knockout attenuates body weight loss and early motor phenotype of HD mice. This study therefore demonstrates that alpha-syn is a modifier of polyQ toxicity in vivo and raises the possibility that potential PD-related therapies aimed to counteract alpha-syn toxicity might help to slow HD. |
