Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins.
Mol Neurodegeneration. 2016-07-28; 11(1):
DOI: 10.1186/s13024-016-0123-2
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1. Mol Neurodegener. 2016 Jul 28;11(1):58. doi: 10.1186/s13024-016-0123-2.
Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7
pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding
proteins.
Alves S(1), Marais T(2), Biferi MG(2), Furling D(2), Marinello M(3)(4), El
Hachimi K(3)(4), Cartier N(5), Ruberg M(3), Stevanin G(3)(4)(6), Brice A(3)(6),
Barkats M(2), Sittler A(7).
Author information:
(1)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. .
(2)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.
(3)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.
(4)EPHE Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, PSL
Universités, 75013, Paris, France.
(5)INSERM UMR1169, MIRCen, 92265, Fontenay aux Roses, France.
(6)Département de Génétique et Cytogénétique, AP-HP, G-H Pitié-Salpêtrière, 47 Bd
de l’Hôpital, 75013, Paris, France.
(7)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. .
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
DOI: 10.1186/s13024-016-0123-2
PMCID: PMC4964261
PMID: 27465358 [Indexed for MEDLINE]