Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease.
Huntington disease (HD) is an adult onset neurodegenerative disorder characterized by selective atrophy and cell loss within the striatum. There is currently no treatment that can prevent the striatal neuropathology. Transglutaminase (TG) activity is increased in HD patients, is associated with cell death, and has been suggested to contribute to striatal neuronal loss in HD. This work assesses the therapeutic potential of cystamine, an inhibitor of TG activity with additional potentially beneficial effects. Specifically, we examine the effect of cystamine on striatal neuronal loss in the YAC128 mouse model of HD. We demonstrate here for the first time that YAC128 mice show a forebrain-specific increase in TG activity compared with wild-type (WT) littermates which is decreased by oral delivery of cystamine. Treatment of symptomatic YAC128 mice with cystamine starting at 7 months prevented striatal neuronal loss. Cystamine treatment also ameliorated the striatal volume loss and striatal neuronal atrophy observed in these animals, but was unable to prevent motor dysfunction or the down-regulation of dopamine and cyclic adenosine monophsophate-regulated phosphoprotein (DARPP-32) expression in the striatum. While the exact mechanism responsible for the beneficial effects of cystamine in YAC128 mice is uncertain, our findings suggest that cystamine is neuroprotective and may be beneficial in the treatment of HD.
Van Raamsdonk
Jeremy M
JM
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics and British Columbia Research Institute for Women and Children's Health, University of British Columbia, Vancouver, British Columbia, Canada.
Pearson
Jacqueline
J
Bailey
Craig D C
CD
Rogers
Daniel A
DA
Johnson
Gail V W
GV
Hayden
Michael R
MR
Leavitt
Blair R
BR
D000284:Administration, Oral; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology; D003538:Cystamine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics*; D016548:Prosencephalon / Q000201:enzymology; D011503:Transglutaminases / Q000378:metabolism
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D011503:Transglutaminases; D003538:Cystamine