title: Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins.
abstract: We used lentiviral vectors (LVs) to generate a new SCA7 animal model overexpressing a truncated mutant ataxin-7 (MUT ATXN7) fragment in the mouse cerebellum, in order to characterize the specific neuropathological and behavioral consequences of the genetic defect in this brain structure.
  
  
  
  LV-mediated overexpression of MUT ATXN7 into the cerebellum of C57/BL6 adult mice induced neuropathological features similar to that observed in patients, such as intranuclear aggregates in Purkinje cells (PC), loss of synaptic markers, neuroinflammation, and neuronal death. No neuropathological changes were observed when truncated wild-type ataxin-7 (WT ATXN7) was injected. Interestingly, the local delivery of LV-expressing mutant ataxin-7 (LV-MUT-ATXN7) into the cerebellum of wild-type mice also mediated the development of an ataxic phenotype at 8 to 12 weeks post-injection. Importantly, our data revealed abnormal levels of the FUS/TLS, MBNL1, and TDP-43 RNA-binding proteins in the cerebellum of the LV-MUT-ATXN7 injected mice. MUT ATXN7 overexpression induced an increase in the levels of the pathological phosphorylated TDP-43, and a decrease in the levels of soluble FUS/TLS, with both proteins accumulating within ATXN7-positive intranuclear inclusions. MBNL1 also co-aggregated with MUT ATXN7 in most PC nuclear inclusions. Interestingly, no MBNL2 aggregation was observed in cerebellar MUT ATXN7 aggregates. Immunohistochemical studies in postmortem tissue from SCA7 patients and SCA7 knock-in mice confirmed SCA7-induced nuclear accumulation of FUS/TLS and MBNL1, strongly suggesting that these proteins play a physiopathological role in SCA7.
  
  
  
  This study validates a novel SCA7 mouse model based on lentiviral vectors, in which strong and sustained expression of MUT ATXN7 in the cerebellum was found sufficient to generate motor defects.
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France. sandropfalves@gmail.com.
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.affiliation: CNRS FRE3617, Center for Research in Myology, Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Institut de Myologie, G-H Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Marais
authors.affiliation: CNRS FRE3617, Center for Research in Myology, Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Institut de Myologie, G-H Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Biferi
authors.affiliation: CNRS FRE3617, Center for Research in Myology, Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Institut de Myologie, G-H Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France.|EPHE Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, PSL Universités, 75013, Paris, France.
authors.forename: Martina
authors.initials: M
authors.lastname: Marinello
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France.|EPHE Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, PSL Universités, 75013, Paris, France.
authors.forename: Khalid
authors.initials: K
authors.lastname: El Hachimi
authors.affiliation: INSERM UMR1169, MIRCen, 92265, Fontenay aux Roses, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France.
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France.|EPHE Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, PSL Universités, 75013, Paris, France.|Département de Génétique et Cytogénétique, AP-HP, G-H Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France.|Département de Génétique et Cytogénétique, AP-HP, G-H Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: CNRS FRE3617, Center for Research in Myology, Sorbonne Universités UPMC Univ Paris 06, INSERM UMRS974, Institut de Myologie, G-H Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités UPMC, Univ Paris 06 UMR_S 1127, ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, 75013, Paris, France. annie.sittler@upmc.fr.
authors.forename: Annie
authors.initials: A
authors.lastname: Sittler
mesh_terms: D000818:Animals; D000067719:Ataxin-7 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics*
chemical_list: D000067719:Ataxin-7; D004268:DNA-Binding Proteins; C493663:MBNL1 protein, human; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins
keywords: Ataxia; Lentiviral vector; RNA binding-proteins; SCA7 mouse model; SCA7 patients