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

被引：58

作者：

Chort, Alice ^{[1
,2
,3
,4
]}

Alves, Sandro ^{[1
,2
,3
,4
]}

Marinello, Martina ^{[1
,2
,3
,4
]}

Dufresnois, Beatrice ^{[1
,2
,3
,4
]}

Dornbierer, Jean-Gabriel ^{[1
,2
,3
,4
]}

Tesson, Christelle ^{[1
,2
,3
,4
,5
]}

Latouche, Morwena ^{[1
,2
,3
,4
]}

Baker, Darren P. ^{[6
]}

Barkats, Martine ^{[7
]}

El Hachimi, Khalid H. ^{[1
,2
,3
,4
,5
]}

Ruberg, Merle ^{[2
]}

Janer, Alexandre ^{[2
]}

Stevanin, Giovanni ^{[1
,2
,3
,4
,5
,8
]}

Brice, Alexis ^{[1
,2
,3
,4
,8
]}

Sittler, Annie ^{[1
,2
,3
,4
]}

机构：

[1] Univ Paris 06, UMR S 975, F-75013 Paris, France

[2] Hop La Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, Ctr Rech, F-75013 Paris, France

[3] INSERM, U975, Paris, France

[4] CNRS, UMR 7225, F-75013 Paris, France

[5] Ecole Prat Hautes Etud, Grp Neurogenet, F-75013 Paris, France

[6] Biogen Idec Inc, Cambridge, MA 02142 USA

[7] Univ Paris 06, UPMC AIM UMR S974, INSERM U974, CNRS UMR 7215,Inst Myol, F-75013 Paris, France

[8] Grp Hosp Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, F-75013 Paris, France

来源：

BRAIN | 2013年 / 136卷

关键词：

interferon beta; SCA7; PML; polyglutamine disease; CAG expansions; HISTONE ACETYLTRANSFERASE ACTIVITY; NEURONAL INTRANUCLEAR INCLUSIONS; CAG REPEAT; NUCLEAR-LOCALIZATION; HUNTINGTONS-DISEASE; TRANSGENIC MICE; NEURODEGENERATIVE DISEASE; SPINOCEREBELLAR ATAXIA-7; POLYGLUTAMINE DISEASES; PROTEIN AGGREGATION;

D O I：

10.1093/brain/awt061

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

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 (R) 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.

引用

页码：1732 / 1745

页数：14

共 70 条

[1]

Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].