title: Interferon β induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.
abstract: 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.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, UMR S 975, 75013 Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Chort
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.forename: Martina
authors.initials: M
authors.lastname: Marinello
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dufresnois
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Dornbierer
authors.forename: Christelle
authors.initials: C
authors.lastname: Tesson
authors.forename: Morwena
authors.initials: M
authors.lastname: Latouche
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.forename: Khalid H
authors.initials: KH
authors.lastname: El Hachimi
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Alexandre
authors.initials: A
authors.lastname: Janer
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Annie
authors.initials: A
authors.lastname: Sittler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000067719:Ataxin-7; D002478:Cells, Cultured; D002648:Child; D055879:Gene Knock-In Techniques; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; C000593832:Atxn7 protein, rat; D009419:Nerve Tissue Proteins; D016899:Interferon-beta
keywords: CAG expansions; PML; SCA7; interferon beta; polyglutamine disease