Paymaan Jafar-Nejad, Maxime W.C. Rousseaux, Alexandra Litvinchuk, Jeehye Park, Ronald Richman, Nan Lu, Urmi Sengupta, Rakez Kayed, Harry T. Orr, Cristian A. Lasagna-Reeves, Marcos J. Guerrero-Muñoz, and Huda Y. Zoghbi
Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded ATAXIN-1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1154Q/+ mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies. DOI: http://dx.doi.org/10.7554/eLife.07558.001, eLife digest Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease in which damage to the brain regions that control movement results in the gradual loss of coordination and motor skills. The disease is a caused by a mutation in the gene that codes for a protein called ATAXIN-1. In healthy individuals this protein contains up to 39 copies of an amino acid called glutamine. However, the mutant gene can encode for 40 or more copies of glutamine, which results in a longer-than-usual ATAXIN-1 protein with toxic properties. Within the brain, some of the toxic ATAXIN-1 proteins form insoluble deposits, while the rest remain soluble. At first it was assumed that the insoluble deposits were responsible for the neurodegeneration seen in SCA1. However, closer examination revealed that these deposits form mainly in brain regions that do not degenerate, which suggests that they might instead have a protective role. This is consistent with evidence from research into other brain disorders, including Alzheimer's disease, which suggests that the soluble form of the toxic proteins might be causing these diseases. Lasagna-Reeves et al. now provide the first direct evidence that the soluble form of the toxic ATAXIN-1 proteins are indeed harmful in a mouse model of SCA1. Experiments reveal that these soluble proteins accumulate in the brain regions that undergo degeneration in SCA1, such as the cerebellum, but not in those regions that remain intact. Moreover, the motor skills and coordination of the mice get worse as the level of soluble toxic ATAXIN-1 increases. Lasagna-Reeves et al. go on to show that a protein called capicua stabilizes the toxic ATAXIN-1 proteins, which keeps them from forming insoluble deposits. Since capicua is particularly abundant in the cerebellum, this could explain the high levels of toxic ATAXIN-1 in this region and why it is vulnerable to degeneration. Future experiments are needed to investigate whether proteins equivalent to capicua might play a similar role in stabilizing toxic proteins in Alzheimer's, Parkinson's and Huntington's diseases, and whether preventing this stabilization could have therapeutic potential. DOI: http://dx.doi.org/10.7554/eLife.07558.002