Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a (CAG) repeat expansion in the coding sequence of ATXN1. The primary mechanism of disease in SCA1 is toxic gain of function by polyglutamine-expanded mutant ATXN1 and is compounded by partial loss of wild-type function. Addressing both disease mechanisms, we have shown that virally expressed RNA interference targeting ATXN1 can both prevent and reverse disease phenotypes in SCA1 mice, and that overexpression of the ATXN1 homolog, ataxin 1-like (ATXN1L), improves disease readouts when delivered pre-symptomatically. Here, we combined these therapeutic approaches into two, dual component recombinant adeno-associated virus (rAAV) vectors and tested their ability to reverse disease in symptomatic SCA1 mice using behavior, pathological, and next-generation sequencing assays. Mice treated with vectors expressing human ATXN1L (hATXN1L) alone showed motor improvements and changes in gene expression that reflected increases in pro-development pathways. When hATN1L was combined with miS1, a previously validated microRNA targeting hATXN1, there was added normalization of disease allele-induced changes in gene expression along with motor improvements. Our data show the additive nature of this two-component approach for a more effective SCA1 therapy. Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a (CAG) repeat expansion in the coding sequence of ATXN1. The primary mechanism of disease in SCA1 is toxic gain of function by polyglutamine-expanded mutant ATXN1 and is compounded by partial loss of wild-type function. Addressing both disease mechanisms, we have shown that virally expressed RNA interference targeting ATXN1 can both prevent and reverse disease phenotypes in SCA1 mice, and that overexpression of the ATXN1 homolog, ataxin 1-like (ATXN1L), improves disease readouts when delivered pre-symptomatically. Here, we combined these therapeutic approaches into two, dual component recombinant adeno-associated virus (rAAV) vectors and tested their ability to reverse disease in symptomatic SCA1 mice using behavior, pathological, and next-generation sequencing assays. Mice treated with vectors expressing human ATXN1L (hATXN1L) alone showed motor improvements and changes in gene expression that reflected increases in pro-development pathways. When hATN1L was combined with miS1, a previously validated microRNA targeting hATXN1, there was added normalization of disease allele-induced changes in gene expression along with motor improvements. Our data show the additive nature of this two-component approach for a more effective SCA1 therapy. IntroductionSpinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by (CAG) expansion within the coding region of the ataxin-1 (ATXN1) gene. In healthy individuals, the (CAG) repeat tract comprises 6–42 repeats interspersed with one to three CAT interruptions. In SCA1 patients, a pure (CAG) expansion of greater than 40 repeats causes disease through toxic protein gain-of-function that is compounded by partial ATXN1 loss-of-function induced by nuclear aggregation and altered protein complex preference.1Lim J. Crespo-Barreto J. Jafar-Nejad P. Bowman A.B. Richman R. Hill D.E. Orr H.T. Zoghbi H.Y. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.Nature. 2008; 452: 713-718Crossref PubMed Scopus (255) Google Scholar, 2Crespo-Barreto J. Fryer J.D. Shaw C.A. Orr H.T. Zoghbi H.Y. Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis.PLoS Genet. 2010; 6: e1001021Crossref PubMed Scopus (100) Google Scholar, 3Duyckaerts C. Durr A. Cancel G. Brice A. Nuclear inclusions in spinocerebellar ataxia type 1.Acta Neuropathol. 1999; 97: 201-207Crossref PubMed Scopus (52) Google Scholar, 4Skinner P.J. Koshy B.T. Cummings C.J. Klement I.A. Helin K. Servadio A. Zoghbi H.Y. Orr H.T. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.Nature. 1997; 389: 971-974Crossref PubMed Scopus (492) Google Scholar Despite ubiquitous ATXN1 expression, neurodegeneration occurs primarily in cerebellar Purkinje cells (PCs) and brainstem nuclei. This pattern is consistent with clinical symptoms of SCA1 which include gait and limb ataxia, dysarthria, and bulbar dysfunction, among others. To date, there are no disease-modifying therapies for SCA1.The B05 mouse is a well-characterized model of SCA1. This transgenic line expresses human ATXN1 (hATXN1) cDNA containing an 82Q poly-glutamine (polyQ) expansion downstream of the PC promoter, Pcp2.5Burright E.N. Clark H.B. Servadio A. Matilla T. Feddersen R.M. Yunis W.S. Duvick L.A. Zoghbi H.Y. Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.Cell. 1995; 82: 937-948Abstract Full Text PDF PubMed Scopus (519) Google Scholar B05 mice develop progressive disease with features similar to SCA1 including impaired motor performance and progressive PC loss.6Clark H.B. Burright E.N. Yunis W.S. Larson S. Wilcox C. Hartman B. Matilla A. Zoghbi H.Y. Orr H.T. Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations.J. Neurosci. 1997; 17: 7385-7395Crossref PubMed Google Scholar,7Robitaille Y. Lopes-Cendes I. Becher M. Rouleau G. Clark A.W. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features.Brain Pathol. 1997; 7: 901-926Crossref PubMed Scopus (117) Google ScholarPrecedence for SCA1 disease reversal was established using a conditional version of the B05 mouse wherein normal cellular and behavioral phenotypes were restored following cessation of mutant ATXN1 expression.8Zu T. Duvick L.A. Kaytor M.D. Berlinger M.S. Zoghbi H.Y. Clark H.B. Orr H.T. Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice.J. Neurosci. 2004; 24: 8853-8861Crossref PubMed Scopus (221) Google Scholar Since this finding, we have shown the potential for disease reversal in B05 animals by miRNA-mediated knockdown of hATXN1 when delivered by recombinant adeno-associated virus (rAAV) directly to the deep cerebellar nuclei (DCN), either disease M.S. therapeutic expression to deep cerebellar for spinocerebellar ataxia type 1 Full Text Full Text PDF PubMed Scopus (52) Google M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google therapeutic approach for SCA1 is overexpression of the ATXN1 ATXN1L with including the both ATXN1 and ATXN1L with the transcriptional A. P.J. an the of mutant J. 24: PubMed Scopus Google Scholar of in a model of SCA1 neuropathology and behavioral through of mutant ATXN1 from native complex with an that cerebellar in A.B. Jafar-Nejad P. Richman R. Fryer J.D. Orr H.T. Zoghbi H.Y. of SCA1 neuropathology by of polyglutamine-expanded ataxin-1 into native Genet. PubMed Scopus Google Scholar, T. C.J. J. K. complex is the primary of cerebellar in spinocerebellar ataxia type 1 through a gain-of-function 97: Full Text Full Text PDF PubMed Scopus Google Scholar, K. B. B. K. M. R. Y. CAG repeat in the mouse SCA1 features and the of protein on Full Text Full Text PDF PubMed Scopus Google Scholar the with the expression of disease phenotypes in B05 and M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google the toxic and loss-of-function of we that hATXN1 knockdown with expression a more than overexpression M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar Here, we the of overexpression alone to that combined ATXN1 knockdown and ATXN1L overexpression in a on in B05 expression of alone with motor in SCA1 dual combined expression within a and in which PC to B05 disease M.S. therapeutic expression to deep cerebellar for spinocerebellar ataxia type 1 Full Text Full Text PDF PubMed Scopus (52) Google M.S. therapies for Spinocerebellar PubMed Scopus Google I. to in and in 17: Full Text Full Text PDF PubMed Scopus Google Scholar The RNA was to the targeting hATXN1, followed downstream by the cDNA for expressed from the 1 M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar was to the to prevent disease when delivered M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar in B05 animals a to from the by of to wild-type H.B. Burright E.N. Yunis W.S. Larson S. Wilcox C. Hartman B. Matilla A. Zoghbi H.Y. Orr H.T. Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations.J. Neurosci. 1997; 17: 7385-7395Crossref PubMed Google M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google Scholar motor in transgenic B05 and were to to either the expression were to the of B05 mice animals a to in a animals either no an to from the to and In animals showed of disease with to to in RNA was from 1 following on cerebellar RNA showed increases in expression with hATXN1 vectors and expression of the ability of therapies to reverse In B05 can in B05 mice of and is to M. M. Orr P. of and in mouse of spinocerebellar ataxia type PubMed Scopus Google Scholar previously showed that this can by M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google Scholar 1 a of were to from in treated with and and by with in have M. Duvick R. P. R. B. Zoghbi H.Y. C. Orr H.T. of ATXN1 transgenic mice SCA1 disease and Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Zoghbi H.Y. Orr H.T. SCA1 to in Purkinje cells of transgenic Genet. 2004; PubMed Scopus Google Scholar, G. M. Purkinje cell expression and SCA1 PubMed Scopus Google Scholar, B. Orr H.T. Zoghbi H.Y. expansion changes in Neurosci. PubMed Scopus Google Scholar motor 1 expression PC and expression in SCA1 T. Duvick L.A. Kaytor M.D. Berlinger M.S. Zoghbi H.Y. Clark H.B. Orr H.T. Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice.J. Neurosci. 2004; 24: 8853-8861Crossref PubMed Scopus (221) Google T. M. K. K. R. M. A. in cerebellar Purkinje cells for and motor PubMed Scopus Google Scholar was in treated with ataxin-1 through the by a in G. M. Purkinje cell expression and SCA1 PubMed Scopus Google M. 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Duvick R. P. R. B. Zoghbi H.Y. C. Orr H.T. of ATXN1 transgenic mice SCA1 disease and Full Text Full Text PDF PubMed Scopus Google J.D. Zoghbi H.Y. Orr H.T. SCA1 to in Purkinje cells of transgenic Genet. 2004; PubMed Scopus Google B. Orr H.T. Zoghbi H.Y. expansion changes in Neurosci. PubMed Scopus Google K. C. Jafar-Nejad P. Shaw C. T. Orr H.T. Zoghbi H.Y. The is altered in spinocerebellar ataxia type 1 and type A. 2008; PubMed Scopus Google of overexpression is in a of the and B05 mice a on gene normalization by with similar and of to a in expression of and to B05 and of gene using previously of that of the were no from following with In the was in the in to overexpression were a gene to progressive PC and in M. Duvick R. P. R. B. Zoghbi H.Y. C. Orr H.T. of ATXN1 transgenic mice SCA1 disease and Full Text Full Text PDF PubMed Scopus Google S. P. J. T. M. M. 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R. B. Zoghbi H.Y. C. Orr H.T. of ATXN1 transgenic mice SCA1 disease and Full Text Full Text PDF PubMed Scopus Google Scholar and of gene expression in a vectors expression of SCA1 and the effects of on the and B05 animals are and were from of the in B05 mice following with and of the expressed following the by by and following with using both and in and function in to and by the of was in was for and previously that vectors can prevent and reverse disease phenotypes in SCA1 M.S. therapeutic expression to deep cerebellar for spinocerebellar ataxia type 1 Full Text Full Text PDF PubMed Scopus (52) Google M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar have shown that overexpression of the ATXN1 homolog, can prevent disease phenotypes when delivered M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar show that a of knockdown and overexpression a more than overexpression alone by the and loss-of-function of behavioral and normalization are of disease using and on these to therapeutic Here, was on treated to molecular by was with from E.N. Clark H.B. Servadio A. Matilla T. Feddersen R.M. Yunis W.S. Duvick L.A. Zoghbi H.Y. Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.Cell. 1995; 82: 937-948Abstract Full Text PDF PubMed Scopus (519) Google Scholar and T. C.J. J. K. complex is the primary of cerebellar in spinocerebellar ataxia type 1 through a gain-of-function 97: Full Text Full Text PDF PubMed Scopus Google Scholar mouse with of include and among of into native complexes the primary of cerebellar in T. C.J. J. K. complex is the primary of cerebellar in spinocerebellar ataxia type 1 through a gain-of-function 97: Full Text Full Text PDF PubMed Scopus Google Scholar and overexpression from these A.B. Jafar-Nejad P. Richman R. Fryer J.D. Orr H.T. Zoghbi H.Y. of SCA1 neuropathology by of polyglutamine-expanded ataxin-1 into native Genet. 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Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis.PLoS Genet. 2010; 6: e1001021Crossref PubMed Scopus (100) Google A.B. Jafar-Nejad P. Richman R. Fryer J.D. Orr H.T. Zoghbi H.Y. of SCA1 neuropathology by of polyglutamine-expanded ataxin-1 into native Genet. PubMed Scopus Google Scholar from the B05 mouse model in this mice ATXN1L from the K. B. B. K. M. R. Y. CAG repeat in the mouse SCA1 features and the of protein on Full Text Full Text PDF PubMed Scopus Google Scholar is that overexpression of alone is to with the in B05 E.N. Clark H.B. Servadio A. Matilla T. Feddersen R.M. Yunis W.S. Duvick L.A. Zoghbi H.Y. Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.Cell. 1995; 82: 937-948Abstract Full Text PDF PubMed Scopus (519) Google Scholar with this we show that of including expression changes have to ATXN1 loss of function on their in and mice among J. Fryer J.D. Shaw C.A. Orr H.T. Zoghbi H.Y. Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis.PLoS Genet. 2010; 6: e1001021Crossref PubMed Scopus (100) Google Scholar than an additive we a in gene when were by and with of by by This a gain of function by that is function through the in animals to of virally delivered in a of ATXN1L of expressing either to B05 mice to performance to from M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar we a by mice similar of vectors within their a mechanism of the the following with both and were in and and from the showed that of is for disease reversal in B05 mice, gene expression, including with M. Duvick R. P. R. B. Zoghbi H.Y. C. Orr H.T. of ATXN1 transgenic mice SCA1 disease and Full Text Full Text PDF PubMed Scopus Google Scholar animals showed gene expression with changes in and In to this in knockdown by from RNA an RNA and of M.S. therapeutic expression to deep cerebellar for spinocerebellar ataxia type 1 Full Text Full Text PDF PubMed Scopus (52) Google M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google M.S. of expression into PubMed Scopus Google M.S. P. of ataxin 1 in for spinocerebellar ataxia type 1 PubMed Scopus Google Scholar we include an in RNA sequencing of from animals treated with to therapeutic effects of in of a RNA for M.S. of expression into PubMed Scopus Google we show that overexpression of is to reverse behavioral following in B05 mice, and gene normalization knockdown of by we that this an of to with established by of a that in a of genetic Our data of both therapeutic into a for of a of both and gain-of-function of disease in and and therapeutic sequence targeting human and Ataxin-1 and the overexpression of ATXN1L have M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar The to virus was by the and an the were from and M.S. of expression into PubMed Scopus Google Scholar and were from with that a the miS1, including the and was into the and vectors were the of and in were by using targeting the were by the of and B05 mice were by T. Orr the of E.N. Clark H.B. Servadio A. Matilla T. Feddersen R.M. Yunis W.S. Duvick L.A. Zoghbi H.Y. Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.Cell. 1995; 82: 937-948Abstract Full Text PDF PubMed Scopus (519) Google Scholar and were by in and are on a pure animals were from from B05 with from were by for the mutant E.N. Clark H.B. Servadio A. Matilla T. Feddersen R.M. Yunis W.S. Duvick L.A. Zoghbi H.Y. Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.Cell. 1995; 82: 937-948Abstract Full Text PDF PubMed Scopus (519) Google Scholar are and include of and were in a and on a with to and of B05 mice were into the to from the and deep from the cerebellar with vectors expressing alone and were delivered in in of mice were with and with for histological were in to for were in in a and for RNA were to 1 and in followed by for were in and and was using to RNA were with and reverse using with for for and a to the region to were using a from on using no with hATXN1 and mouse were using and and using CAT and and and RNA was from using and treated to using were using RNA in were using RNA for was using combined and RNA were for the cDNA were using the were on with to and were and of 1 on a cell using The sequencing in were to the from was with the A. C.A. J. C. S. P. M. PubMed Scopus Google Scholar by were the for expression using version version S. of and for data with PubMed Scopus Google Scholar T. S. M. P. T. a for Google Scholar was for was in and within and cerebellar were in with were on for for protein was using a were into and to for were for 1 in in was in in and followed by in in were using were using mouse in followed by in was of to and mice were to the for with Mice were tested in three by a of for The of from to 40 followed by a 40 for a of to was the when mice from the on for Mice on the of the were and were to B05 mice among and followed by was to IntroductionSpinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by (CAG) expansion within the coding region of the ataxin-1 (ATXN1) gene. In healthy individuals, the (CAG) repeat tract comprises 6–42 repeats interspersed with one to three CAT interruptions. In SCA1 patients, a pure (CAG) expansion of greater than 40 repeats causes disease through toxic protein gain-of-function that is compounded by partial ATXN1 loss-of-function induced by nuclear aggregation and altered protein complex preference.1Lim J. Crespo-Barreto J. Jafar-Nejad P. Bowman A.B. Richman R. Hill D.E. Orr H.T. Zoghbi H.Y. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.Nature. 2008; 452: 713-718Crossref PubMed Scopus (255) Google Scholar, 2Crespo-Barreto J. Fryer J.D. Shaw C.A. Orr H.T. Zoghbi H.Y. Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis.PLoS Genet. 2010; 6: e1001021Crossref PubMed Scopus (100) Google Scholar, 3Duyckaerts C. Durr A. Cancel G. Brice A. Nuclear inclusions in spinocerebellar ataxia type 1.Acta Neuropathol. 1999; 97: 201-207Crossref PubMed Scopus (52) Google Scholar, 4Skinner P.J. Koshy B.T. Cummings C.J. Klement I.A. Helin K. Servadio A. Zoghbi H.Y. Orr H.T. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.Nature. 1997; 389: 971-974Crossref PubMed Scopus (492) Google Scholar Despite ubiquitous ATXN1 expression, neurodegeneration occurs primarily in cerebellar Purkinje cells (PCs) and brainstem nuclei. This pattern is consistent with clinical symptoms of SCA1 which include gait and limb ataxia, dysarthria, and bulbar dysfunction, among others. To date, there are no disease-modifying therapies for SCA1.The B05 mouse is a well-characterized model of SCA1. This transgenic line expresses human ATXN1 (hATXN1) cDNA containing an 82Q poly-glutamine (polyQ) expansion downstream of the PC promoter, Pcp2.5Burright E.N. Clark H.B. Servadio A. Matilla T. Feddersen R.M. Yunis W.S. Duvick L.A. Zoghbi H.Y. Orr H.T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.Cell. 1995; 82: 937-948Abstract Full Text PDF PubMed Scopus (519) Google Scholar B05 mice develop progressive disease with features similar to SCA1 including impaired motor performance and progressive PC loss.6Clark H.B. Burright E.N. Yunis W.S. Larson S. Wilcox C. Hartman B. Matilla A. Zoghbi H.Y. Orr H.T. Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations.J. Neurosci. 1997; 17: 7385-7395Crossref PubMed Google Scholar,7Robitaille Y. Lopes-Cendes I. Becher M. Rouleau G. Clark A.W. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features.Brain Pathol. 1997; 7: 901-926Crossref PubMed Scopus (117) Google ScholarPrecedence for SCA1 disease reversal was established using a conditional version of the B05 mouse wherein normal cellular and behavioral phenotypes were restored following cessation of mutant ATXN1 expression.8Zu T. Duvick L.A. Kaytor M.D. Berlinger M.S. Zoghbi H.Y. Clark H.B. Orr H.T. Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice.J. Neurosci. 2004; 24: 8853-8861Crossref PubMed Scopus (221) Google Scholar Since this finding, we have shown the potential for disease reversal in B05 animals by miRNA-mediated knockdown of hATXN1 when delivered by recombinant adeno-associated virus (rAAV) directly to the deep cerebellar nuclei (DCN), either disease M.S. therapeutic expression to deep cerebellar for spinocerebellar ataxia type 1 Full Text Full Text PDF PubMed Scopus (52) Google M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google therapeutic approach for SCA1 is overexpression of the ATXN1 ATXN1L with including the both ATXN1 and ATXN1L with the transcriptional A. P.J. an the of mutant J. 24: PubMed Scopus Google Scholar of in a model of SCA1 neuropathology and behavioral through of mutant ATXN1 from native complex with an that cerebellar in A.B. Jafar-Nejad P. Richman R. Fryer J.D. Orr H.T. Zoghbi H.Y. of SCA1 neuropathology by of polyglutamine-expanded ataxin-1 into native Genet. PubMed Scopus Google Scholar, T. C.J. J. K. complex is the primary of cerebellar in spinocerebellar ataxia type 1 through a gain-of-function 97: Full Text Full Text PDF PubMed Scopus Google Scholar, K. B. B. K. M. R. Y. CAG repeat in the mouse SCA1 features and the of protein on Full Text Full Text PDF PubMed Scopus Google Scholar the with the expression of disease phenotypes in B05 and M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google the toxic and loss-of-function of we that hATXN1 knockdown with expression a more than overexpression M.S. R. P. and phenotypes induced by mutant human PubMed Scopus Google M.S. therapies for Spinocerebellar PubMed Scopus Google Scholar Here, we the of overexpression alone to that combined ATXN1 knockdown and ATXN1L overexpression in a on in B05

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