We showed previously, in a cell model of
spinocerebellar ataxia 7, that
interferon beta 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 ataxia 7. We now show that
interferon beta also induces PML-dependent clearance of
ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant
ataxin 7 in the mice induces itself the expression of endogenous
interferon beta and its receptor. Immunohistological studies in brains from two patients with
spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans.
Interferon beta, 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 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive
gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with
spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients:
ataxin 7-positive neuronal intranuclear inclusions that were reduced by
interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant
ataxin 7 that
interferon beta treatment improves Purkinje cell survival.