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

Alice Chort, Sandro Alves, Martina Marinello, Béatrice Dufresnois, Jean-Gabriel Dornbierer, Christelle Tesson, Morwena Latouche, Darren P. Baker, Martine Barkats, Khalid H. El Hachimi, Merle Ruberg, Alexandre Janer, Giovanni Stevanin, Alexis Brice, Annie Sittler
Brain. 2013-03-21; 136(6): 1732-1745
DOI: 10.1093/brain/awt061

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1. Brain. 2013 Jun;136(Pt 6):1732-45. doi: 10.1093/brain/awt061. Epub 2013 Mar 21.

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

Chort A(1), Alves S, Marinello M, Dufresnois B, Dornbierer JG, Tesson C, Latouche
M, Baker DP, Barkats M, El Hachimi KH, Ruberg M, Janer A, Stevanin G, Brice A,
Sittler A.

Author information:
(1)Université Pierre et Marie Curie-Paris 6, UMR S 975, 75013 Paris, France.

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.

DOI: 10.1093/brain/awt061
PMID: 23518714 [Indexed for MEDLINE]

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