Huntingtin and Huntingtin-Associated Protein 1 Influence Neuronal Calcium Signaling Mediated by Inositol-(1,4,5) Triphosphate Receptor Type 1

Abstract

Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin (Htt). The type 1 inositol (1,4,5)-triphosphate receptor (InsP3R1) is an intracellular calcium (Ca2+) release channel that plays an important role in neuronal function. In a yeast two-hybrid screen with the InsP3R1 carboxy terminus, we isolated Htt-associated protein-1A (HAP1A). We show that an InsP3R1-HAP1A-Htt ternary complex is formed in vitro and in vivo. In planar lipid bilayer reconstitution experiments, InsP3R1 activation by InsP3 is sensitized by Httexp, but not by normal Htt. Transfection of full-length Httexp or caspase-resistant Httexp, but not normal Htt, into medium spiny striatal neurons faciliates Ca2+ release in response to threshold concentrations of the selective mGluR1/5 agonist 3,5-DHPG. Our findings identify a novel molecular link between Htt and InsP3R1-mediated neuronal Ca2+ signaling and provide an explanation for the derangement of cytosolic Ca2+ signaling in HD patients and mouse models.

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

“…Dysregulation of ER Ca 2ϩ homeostasis occurs as an early event during many forms of apoptosis and has been implicated in the pathophysiology of several neurodegenerative diseases including Alzheimer's, Huntington's, and prion diseases (6,34,35). Several different agents that evoke ER stress including Ca 2ϩ ionophores and thapsigargin have been shown to disrupt intracellular Ca 2ϩ homeostasis, suggesting a central role for Ca 2ϩ in ER stressinduced apoptosis.…”

“…Studies employing specific proteasomal inhibitors will further elucidate possible mechanisms by which Herp stabilizes ER calcium homeostasis under conditions associated with ER stress. Alternatively, Herp may inhibit the sustained ER Ca 2ϩ release during ER stress by inhibiting the association of the ER Ca 2ϩ release channels with pathophysiological ligands including the huntington-associated protein 1 (35) and cytochrome c (57).…”

“…7C), suggesting that cleavage of Herp in cells subjected to ER stress requires activation of a caspase(s). Next, we assayed the ability of purified recombinant caspase 3 to cleave 35 S-labeled, in vitro transcribed/translated Herp. The results shown in Fig.…”

ER stress and neurodegenerative diseases

“…58 Mutant huntingtin can affect calcium metabolism in the cell and sensitize the IP3 receptors at the ER. 59 One piece of evidence for the role of ER stress in polyQ diseases comes from studies showing colocalization of polyQ fragments with various molecular chaperones, such as Hsp70 and Hsp40 that are induced in ER stress. 58 In addition, overexpression of Hsp70 suppresses polyQ toxicity in Drosophila.…”

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

“…Deletion of the genes encoding the type 1 IP 3 R (IP 3 R1) leads to perturbations in long-term potentiation/ depression (3,10,11) and spinogenesis (12), and the human genetic disease spinocerebellar ataxia 15 is caused by haploinsufficiency of the IP 3 R1 gene (13)(14)(15). Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16)(17)(18)) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23,24), autophagy regulation (24)(25)(26)(27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophage inflammasomes (31).…”