title: Broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei: implications for spinocerebellar ataxia type 1 therapy.
abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, late-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin-1 protein, which causes progressive neurodegeneration in cerebellar Purkinje cells and brainstem nuclei. Here, we tested if reducing mutant ataxin-1 expression would significantly improve phenotypes in a knock-in (KI) mouse model that recapitulates spatial and temporal aspects of SCA1. Adeno-associated viruses (AAVs), expressing inhibitory RNAs targeting ataxin-1, were injected into the deep cerebellar nuclei (DCN) of KI mice. This approach induced ataxin-1 suppression in the cerebellar cortex and in brainstem neurons. RNA interference (RNAi) of ataxin-1 preserved cerebellar lobule integrity and prevented disease-related transcriptional changes for over a year. Notably, RNAi therapy also preserved rotarod performance and neurohistology. These data suggest that delivery of AAVs encoding RNAi sequences against ataxin-1, to DCN alone, may be sufficient for SCA1 therapy.
authors.affiliation: Neuroscience Training Program, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Keiser
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Boudreau
authors.affiliation: Neuroscience Training Program, University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Neurology, University of Iowa, Iowa City, Iowa, USA; Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA. Electronic address: beverly-davidson@uiowa.edu.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002525:Cerebellar Cortex / Q000378:metabolism*; D002529:Cerebellar Nuclei / Q000821:virology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D034622:RNA Interference; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology* / Q000628:therapy
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins