Deranged neuronal calcium signaling and Huntington disease.
Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Httexp and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Httexp and deranged Ca2+ signaling in MSN neurons. Experimental evidence indicates that (1) Ca2+ homeostasis is abnormal in mitochondria isolated from lymphoblasts of HD patients and from brains of the YAC72 HD mouse model; (2) Httexp leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in MSN from YAC72 HD mouse model; and (3) Httexp binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) carboxy-terminus and causes sensitization of InsP3R1 to activation by InsP3 in planar lipid bilayers and in MSN. Based on these results we propose that Httexp-induced cytosolic and mitochondrial Ca2+ overload of MSN plays an important role in the pathogenesis of HD and that Ca2+ signaling blockers may play a beneficial role in treatment of HD.
Bezprozvanny
Ilya
I
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Ilya.Bezprozvanny@UTSouthwestern.edu
Hayden
Michael R
MR
D000818:Animals; D017209:Apoptosis; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D042622:DNA Repeat Expansion; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D015220:Calcium Channels; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D016194:Receptors, N-Methyl-D-Aspartate