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 Htt(exp) and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Htt(exp) 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) Htt(exp) leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in NISN from YAC72 HD mouse model; and (3) Htt(exp) binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) carboxy-terminus and causes sensitization of InsP(3)R1 to activation by InsP(3) in planar lipid bilayers and in MSN. Based on these results we propose that Htt(exp)- 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. (C) 2004 Elsevier Inc. All rights reserved.