Dopaminergic signaling and striatal neurodegeneration in Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disorder caused by polyglutamine (polyQ) expansion in Huntingtin protein (Htt). PolyQ expansion in Htt(exp) causes selective degeneration of striatal medium spiny neurons (MSNs) in HD patients. Striatal MSN neurons receive glutamatergic input from the cortex and dopaminergic input from the substantia nigra. In previous studies with the yeast artificial chromosome (YAC128) transgenic HD mouse model, we established a connection between glutamate receptor activation, disturbed calcium (Ca2+) signaling, and apoptosis of HD MSNs (Tang et al., 2005). Here, we used the same YAC128 mouse model to investigate the role of dopaminergic signaling in HD. We discovered that glutamate and dopamine signaling pathways act synergistically to induce elevated Ca2+ signals and to cause apoptosis of YAC128 MSNs in vitro. We demonstrated that potentiating effects of dopamine are mediated by D1-class dopamine receptors (DARs) and not by D2-class DARs. Consistent with in vitro findings, in whole-animal experiments we found that persistent elevation of striatal dopamine levels exacerbated the behavioral motor deficits and MSN neurodegeneration in YAC128 mice. We further discovered that the clinically relevant dopamine pathway inhibitor tetrabenazine alleviated the motor deficits and reduced striatal cell loss in YAC128 mice. Our results suggest that dopamine signaling pathway plays an important role in HD pathogenesis and that antagonists of dopamine pathway such as tetrabenazine or dopamine receptor blockers may have a therapeutic potential for treatment of HD beyond well established "symptomatic" benefit.
Tang
Tie-Shan
TS
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Chen
Xi
X
Liu
Jing
J
Bezprozvanny
Ilya
I
D000818:Animals; D018244:Chromosomes, Artificial, Yeast; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000502:physiology*; D005260:Female; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D004298:Dopamine