Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice

We showed previously, in a cell model of spinocerebellar ataxia7, that interferonbeta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia7. We now show that interferonbeta also induces PML-dependent clearance of ataxin 7in a preclinical model, SCA7266Q/5Q knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7in the mice induces itself the expression of endogenous interferonbeta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia7 confirmed that these modifications are also caused by the disease in humans. Interferonbeta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosisor other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7266Q/5Q knock-in mice was significantly improved on two behavioural tests sensitiveto cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordinationand fine movements, which are affected in patients with spinocerebellar ataxia7. In addition to motor dysfunction, SCA7266Q/5Q mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferonbeta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7266Q/5Q mice, we showed in primary cell cultures expressing mutant ataxin 7that interferonbeta treatment improves Purkinje cell survival. * Abbreviations : DAB : 3,3’- diaminobenzidine DAPI: 4',6-diamidino- 2-phenylindoleMSA : murine serum albumin SCA : spinocerebellar ataxia