Abstract
BackgroundWe 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.ResultsLV-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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0123-2) contains supplementary material, which is available to authorized users.
Highlights
We used lentiviral vectors (LVs) to generate a new Spinocerebellar ataxia type 7 (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
SCA7 is caused by an unstable CAG repeat expansion in the coding region of the SCA7 gene conferring a toxic gain of function to the ataxin-7 (ATXN7) protein which accumulates aberrantly in neurons, a mechanism involved in a family of eight other inherited neurodegenerative polyglutamine (PolyQ) diseases, including Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral pallidoluysian atrophy (DRPLA), spinocerebellar ataxia (SCA) types 1, 2, 3, 6 and 17 [4]
We initially focused on the RNA-binding proteins (RBPs) Fused in sarcoma (FUS/TLS), found to be mutated in familial amyotrophic lateral sclerosis (ALS) [19], since it was shown to be a major component of nuclear aggregates in several polyQ disorders, such as HD, SCA1 and SCA3 [20, 21]
Summary
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. Patients present with cerebellar ataxia due to moderate to severe neuronal loss and gliosis in the cerebellum, especially Purkinje cells, inferior olivary, dentate nucleus and pontine nuclei, and to a lesser extent in the globus pallidus, substantia nigra and red nucleus. They present with visual impairment due to degeneration of cone and rod photoreceptors [1,2,3]. Local overexpression of mutant proteins using viral vectors has been a successful strategy to model polyQ pathologies of the central nervous system (CNS), such as HD [17] and SCA3 [18], generating robust in vivo genetic models leading to neuronal degeneration in well-defined brain regions
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