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Related Concept Videos

Huntington Disease l: Introduction01:21

Huntington Disease l: Introduction

Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...
IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...

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Related Experiment Video

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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington's disease.

I Bezprozvanny1

  • 1Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Ilya.Bezprozvanny@UTSouthwestern.edu

Sub-Cellular Biochemistry
|January 16, 2008
PubMed
Summary

Huntington's disease (HD) involves mutant huntingtin (Htt) protein binding to the inositol trisphosphate receptor (InsP3R1), disrupting calcium signaling. This discovery offers new therapeutic targets for treating this neurodegenerative disorder.

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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder affecting medium spiny striatal neurons (MSN).
  • HD pathogenesis is linked to polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, but the precise mechanism causing MSN neurodegeneration is unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which mutant huntingtin (Htt) protein contributes to neurodegeneration in Huntington's disease.
  • To explore the role of intracellular calcium (Ca2+) signaling pathways in HD pathogenesis.

Main Methods:

  • Investigated the interaction between mutant Htt(exp) and the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) in vitro and in primary MSN.
  • Assessed the functional consequences of Htt(exp)-InsP3R1 interaction on InsP3R1 activation and neuronal Ca2+ signaling.
  • Examined the relationship between aberrant Ca2+ signaling and MSN apoptosis in a mouse model of HD (YAC128).

Main Results:

  • Mutant Htt(exp) protein specifically binds to the carboxy-terminal region of InsP3R1.
  • Htt(exp) binding sensitizes InsP3R1 to activation by InsP3, leading to altered Ca2+ release in MSN.
  • Abnormal Ca2+ signaling was directly linked to MSN apoptosis in the YAC128 HD mouse model.
  • Mutant Htt(exp) was also found to activate NR2B-containing NMDA receptors.

Conclusions:

  • Deranged neuronal Ca2+ signaling, particularly involving InsP3R1, plays a critical role in the pathogenesis of Huntington's disease.
  • InsP3R1 and other Ca2+ signaling modulators represent promising therapeutic targets for HD treatment.