title: Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis.
abstract: OBJECTIVE
  Huntington disease-like 2 (HDL2) is a progressive, late onset autosomal dominant neurodegenerative disorder, with remarkable similarities to Huntington disease (HD). HDL2 is caused by a CTG/CAG repeat expansion. In the CTG orientation, the repeat is located within the alternatively spliced exon 2A of junctophilin-3 (JPH3), potentially encoding polyleucine and polyalanine, whereas on the strand antisense to JPH3, the repeat is in frame to encode polyglutamine. The JPH3 protein product serves to stabilize junctional membrane complexes and regulate neuronal calcium flux. We have previously demonstrated the potential pathogenic properties of JPH3 transcripts containing expanded CUG repeats. The aim of this study was to test the possibility that loss of JPH3 expression or expanded amino acid tracts also contribute to HDL2 pathogenesis.
  
  
  METHODS
  Transcripts from the HDL2 locus, and their protein products, were examined in HDL2, HD, and control frontal cortex. The effect of loss of Jph3 was examined in mice with partial or complete loss of Jph3.
  
  
  RESULTS
  Bidirectional transcription occurs at the HDL2 locus, although expression of antisense transcripts with expanded CAG repeats is limited. Protein products with expanded amino acid tracts were not detected in HDL2 brain. However, JPH3 transcripts and full-length JPH3 protein are decreased in HDL2 brain, and Jph3 hemizygous and null mice exhibit abnormal motor function.
  
  
  CONCLUSIONS
  Our results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of JPH3 RNA and a toxic loss of JPH3 expression.
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Seixas
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holmes
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.forename: Amira
authors.initials: A
authors.lastname: Pavlovich
authors.forename: Nancy
authors.initials: N
authors.lastname: Sachs
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Pruitt
authors.forename: Isabel
authors.initials: I
authors.lastname: Silveira
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.forename: Dobrila D
authors.initials: DD
authors.lastname: Rudnicki
mesh_terms: D017668:Age of Onset; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009483:Neuropsychological Tests; D016376:Oligonucleotides, Antisense / Q000235:genetics; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; C412507:junctophilin