title: Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model.
abstract: BACKGROUND
  Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1(154Q/2Q) mice) that replicates many features of the human disease.
  
  
  RESULTS
  Sca1(154Q/2Q) mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1(154Q/2Q) mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity.
  
  
  CONCLUSIONS
  The effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.
authors.affiliation: 21st Century COE program on Brain Integration and Its Disorders, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Watase
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gatchel
authors.forename: Yaling
authors.initials: Y
authors.lastname: Sun
authors.forename: Effat
authors.initials: E
authors.lastname: Emamian
authors.forename: Richard
authors.initials: R
authors.lastname: Atkinson
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D000067696:Ataxin-1; D000067528:Ataxins; D003712:Dendrites / Q000201:enzymology / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000473:pathology; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011496:Protein Methyltransferases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*
chemical_list: C000593749:ATXN1 protein, human; D018692:Antimanic Agents; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016651:Lithium Carbonate; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3