Varshney A, Ehrlich BE.
Intracellular Ca2+ signaling and human disease: the hunt begins with Huntington's.
Neuron. 2003 Jul 17;39(2):195-7.
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This series of well-designed experiments shows that mutant forms of huntingtin (Htt) with expanded polyglutamines can, under certain circumstances, sensitize Inositol (1,4,5) triphosphate receptors (Ins3PR) to activation by InsP3. These InsP3 receptors line the limiting membranes of the endoplasmic reticulum, in which high concentrations of calcium are stored. The authors propose that median spiny neurons of huntingtin patients might be especially
susceptible to calcium-induced cell death due to enhanced release of calcium into the cytoplasm from ER stores via InsP3 receptors that are activated by the normal NMDR-mediated calcium signaling mechanism. Only a mutant, expanded form of Htt was able to sensitize the ER-based Ins3P receptors. However, when planar lipid bilayer experiments were performed, wild-type Htt was also able to sensitize Ins3P receptors if a protein that associates with Htt, called HAP1, was added to the system. This complicating factor suggests that these interesting experiments offer the first insights into what is likely to be a complex series of interactions between mutant forms of Htt and the proteins that regulate the intracytoplasmic release of ionic calcium.
This manuscript describes studies done by Tang et al. to uncover potential mechanisms for the neuronal cell death that occurs in Huntington's disease. These researchers are the first to show that
huntingtin (the protein that, when mutated, causes Huntington's disease) can form a multimeric complex with huntingtin-associated protein 1 (HAP1A) and with the inositol-(1,4,5)-triphosphate receptor (IP3Rc, a
calcium release channel found on the endoplasmic reticulum) in vivo. More importantly, the authors discovered that this interaction has functional consequences for IP3Rc function, and therefore calcium
handling in neurons, and that these effects are magnified when mutant huntingtin is present. This work is exciting because it opens up a whole new area of investigation with regard to potential therapies for this devastating disease.