Deranged neuronal calcium signaling and Huntington disease

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Abstract

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.

Section snippets

Huntington disease and huntingtin

Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder with the age of onset between 35 and 50 years and inexorable progression to death 15–20 years after onset. The symptoms include motor abnormalities including chorea and psychiatric disturbance with gradual dementia [1]. Neuropathological analysis reveals selective and progressive neuronal loss in the striatum (caudate nucleus, putamen, and globus pallidus) [1], [2]. GABAergic medium spiny striatal neurons (MSN) are the

Httexp disrupts mitochondrial Ca2+ homeostasis

Striatal-specific defects of mitochondrial respiratory chain activity have been described in postmortem brains of HD patients and in brains from R6/2 HD mouse model [18], [19], [20], [21]. In addition to their role in energy production and metabolism, mitochondria also play an important role in cellular Ca2+ homeostasis [22], [23]. Mitochondria isolated from lymphoblasts of HD patients and from brains of HD YAC72 transgenic mouse models revealed pronounced defects in Ca2+ handling [24]. In

Httexp activates NR1/NR2B NMDAR

Glutamate activates three classes of ionotropic glutamate receptors (AMPA receptors, kainate receptors, and NMDA receptors). Activation of NMDAR results in significant Ca2+ influx, and overstimulation of NMDAR may lead to Ca2+ overload and neuronal cell death (glutamate excitotoxicity). Several lines of evidence indicate that glutamate-mediated excitotoxicity plays a role in neurodegeneration of HD MSN. Striatal injection of kainic acid induced death of MSN and yielded one of the first animal

Httexp sensitizes InsP3R1 to InsP3

The inositol (1,4,5)-triphosphate receptor (InsP3R) is an intracellular calcium (Ca2+) release channel that plays an important role in neuronal Ca2+ signaling [43]. Three isoforms of InsP3R have been identified [44]. The type 1 receptor (InsP3R1) is the predominant neuronal isoform. Mice lacking InsP3R1 display severe ataxic behavior [45], and mice with a spontaneous mutation in the InsP3R1 gene experience convulsions and ataxia [46], suggesting a major role of InsP3R1 in neuronal function. In

Httexp causes cytosolic and mitochondrial Ca2+ overload and apoptosis of HD MSN

Ca2+ overload plays a central role in apoptosis [54], [55], [56], [57]. ER and cytosolic Ca2+ levels influence activity of Bcl/Bax family members and Ca2+ overload of mitochondria leads to opening of the permeability transition pore (PTP) and release of cytochrome c, AIF, Ca2+, and other pro-apoptotic factors into cytoplasm. Interestingly, imaging studies suggested that Ca2+ released from ER via InsP3R is preferentially accumulated in the mitochondria [23], indicating that upregulation of InsP3

Future perspectives

Despite efforts by many laboratories, there is no cure for HD. Our hypothesis (Fig. 5) suggests that Ca2+ signaling blockers, such as NR2B-specific inhibitors of NMDAR and blockers of mGluR5 and InsP3R1, may be beneficial for the treatment of HD. Inhibitors of Httexp association with InsP3R1 may potentially be used as a more specific HD therapeutic. These concepts are being tested in our laboratories in a YAC128 mouse model that reproduces selective late-onset MSN neurodegeneration as observed

Acknowledgments

I.B. is supported by the Robert A. Welch Foundation, Huntington’s Disease Society of America, Hereditary Disease Foundation, and NIH R01 NS38082. M.R.H. is supported by the Canadian Institutes of Health Research, Hereditary Disease Foundation, and Huntington’s Disease Society of America, the High Q Foundation, the Huntington Society of Canada, and holds a Canada Research Chair in Human Genetics.

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