Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in ataxin-3 (ATX3; MJD1) protein. In biochemical experiments, we demonstrate that mutant ATX3(exp) specifically associated with the type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1), an intracellular calcium (Ca(2+)) release channel. In electrophysiological and Ca(2+) imaging experiments, we show that InsP(3)R1 was sensitized to activation by InsP(3) in the presence of mutant ATX3(exp). We found that feeding SCA3-YAC-84Q transgenic mice with dantrolene, a clinically relevant stabilizer of intracellular Ca(2+) signaling, improved their motor performance and prevented neuronal cell loss in pontine nuclei and substantia nigra regions. Our results indicate that deranged Ca(2+) signaling may play an important role in SCA3 pathology and that Ca(2+) signaling stabilizers such as dantrolene may be considered as potential therapeutic drugs for treatment of SCA3 patients.
Chen
Xi
X
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Tang
Tie-Shan
TS
Tu
Huiping
H
Nelson
Omar
O
Pook
Mark
M
Hammer
Robert
R
Nukina
Nobuyuki
N
Bezprozvanny
Ilya
I
D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D017827:Machado-Joseph Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009125:Muscle Relaxants, Central / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009687:Nuclear Proteins / Q000235:genetics*; D011149:Pons / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D009125:Muscle Relaxants, Central; D009687:Nuclear Proteins; D014157:Transcription Factors; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D003620:Dantrolene