Differential Levels and Phosphorylation of Type 1 Inositol 1,4,5-Trisphosphate Receptor in Four Different Murine Models of Huntington Disease

Abstract

Background: The intracellular ion channel type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1) releases Ca 2+ from the endoplasmic reticulum upon stimulation with IP 3 . Perturbation of IP 3 R1 has been implicated in the development of several neurodegenerative disorders, including Huntington disease (HD). Objective: To elucidate the putative role of IP 3 R1 phosphorylation in HD, we investigated IP 3 R1 levels and protein phosphorylation state in the striatum, hippocampus and cerebellum of four murine HD models. Methods: Quantitative immunoblotting with antibodies to IP 3 R1 protein and its phosphorylated serines 1589 and 1755 was applied to brain homogenates from R6/1 mice to study early-onset aggressive HD. To determine if IP 3 R1 changes precede overt pathology, we immunostained tissues from the regions of interest and several control regions for IP 3 R1 in tgHD CAG51n rats and BACHD and zQ175DNKI mice, all recognized models for late-onset HD. Results: R6/1 mice had reduced total IP 3 R1 immunoreactivity, variably reduced serine1755-phosphorylation in all regions investigated, and reduced serine1589-phosphorylation in cerebellum. IP 3 R1 levels were decreased relative to cell-specific marker proteins. In tgHD CAG51n rats we found reduced IP 3 R1 levels in the cerebellum, but otherwise unchanged IP 3 R1 phosphorylation and protein levels. In BACHD and zQ175DNKI mice only age-dependent decline of IP 3 R1 was observed. Conclusion:The level and phosphorylation of IP 3 R1 is reduced to a variable degree in the different HD models relative to control, indicating that earlier findings in more aggressive exon 1-truncated HD models may not be replicated in models with higher construct validity. Further analysis of possible coupling of reduced IP 3 R1 levels with development of neuropathological responses and cell-specific degeneration is warranted.

Cyclitols: From Basic Understanding to Their Association with Neurodegeneration

“…One of the enzymes that can disturb IP3R's allostery is transglutaminase type 2 (TG2) and its regulation is based on the covalent posttranslational modification of the Gln2746 residue which TG2 tethers to the communicating subunit [94]. Both Gln2746 changes and IP3R dysregulation were detected in HD models, confirming the involvement of IP3R dysregulation in disease pathogenesis [29,95]. TG2 ablation in model mice prolonged their lifespan and improved motor function [25].…”