Huntington's Disease Research

Huntington's disease is a neurodegenerative disease characterized by cognitive decline, psychiatric disturbances and motor dysfunction. It is a monogenetic disorder that results in the production of mutant huntingtin protein (mHTT) mRNA and protein. The aberrant HTT mRNA and protein cause cellular stress that results in synaptic loss and, eventually, apoptosis. Striatal and cortical atrophy is a major hallmark of Huntington's disease, along with mHTT RNA and protein aggregates, which form RNA foci and inclusion bodies in the cell, respectively.

Research Areas
Literature (4)
Genetic Basis of Huntington's Disease

Huntington's disease exhibits high penetrance, meaning that those who inherit the mutant allele will have the disease. The prevalence of Huntington's disease is 2.7 individuals per 100,000. Disease onset normally occurs between the ages of 35 and 50, but both age of onset and the severity and speed of disease progression is highly variable.

The ubiquitously expressed huntingtin protein is encoded by the IT15 gene. Huntington's disease is classified as a trinucleotide repeat disorder because it arises from the repetition of a three base sequence (CAG). These expanded repeats generate a series of glutamine residues, also known as a polyglutamine tract (polyQ). If the number of CAG codons exceeds a threshold of 35 repeats, the protein encoded by the altered gene (mHTT) will be different to the normal protein product (HTT). This is particularly important when considering the genetic basis of Huntington's disease, as the number of repeats is not fixed and may vary between generations (intergenerational instability) or within the same cell over time (somatic instability). The instability of the CAG region has been shown to result from faulty DNA damage repair. As the length of the repeat is positively correlated with the age of onset of disease and severity of symptoms, slowing or stopping somatic instability could provide a much sought after disease-modifying therapy.

Huntingtin protein is cleaved within the N-terminal region by calpains, a process to which it is more susceptible as the length of the polyQ tract increases. Caspases have also been linked to the proteolysis of HTT. The nature of this cleavage is of particular interest, since the cleavage products (the neurotoxic N-terminal fragments) can sequester other proteins to form aggregates in the neuronal cytoplasm and nuclei, known as inclusion bodies. These aggregates can cause transcriptional dysregulation, dysfunction of proteasomes, nuclear-cytoplasmic transport and transcription, and gradually impede neurotransmission to the extent that neurotransmitter vesicles cannot move within the cytoskeleton. In addition to vesicular movement, mHTT also impairs mitochondrial trafficking. Neuronal dysfunction and/or death results, and the role of autophagy in the breakdown of these aggregates becomes even more emphasized; debate over the neuroprotective capacity of these aggregates means that the precise role of autophagy in Huntington's disease is yet to be fully characterized. Mutations at the calpain cleavage sites prevent the aggregation and toxicity of HTT protein; furthermore, proteolysis of mHTT by caspase-6 is also linked to neuronal dysfunction and neurodegeneration.

Cellular Consequences of Huntington's Disease

Huntington's disease primarily affects striatal medium spiny neurons (MSNs), GABAergic neurons that receive both glutamate signals from the cortex and dopamine signals from the substantia nigra. A long-standing hypothesis postulates that high levels of excitatory neurotransmitters and/or activation of glutamate receptors (in particular the NMDA receptor) sensitize MSNs to cytotoxic cell death. Mutant HTT is thought to decrease the expression of glutamate transporters and enhance the activity and toxicity of NMDA receptors (in particular NR1 and NR2B), thus causing striatal degeneration. A combination of glutamatergic afferents and unique NMDA receptor subtype composition in MSNs could, in part, confer their vulnerability to degeneration in Huntington's disease. Modifying the release of glutamate or dopamine is also shown to alter Huntington's disease pathology: for example, administration of L-DOPA or knockout of the dopamine transporter - both of which increase dopamine levels - increases loss of MSNs, and attenuation of glutamate activity helps restore MSN function.

Cognitive ability is also impaired in those with Huntington's disease, and cognitive deficits often occur before movement problems become apparent. However, the current FDA approved treatments for Huntington's disease only alleviate motor symptoms, namely chorea, a form of dyskinesia characterized by involuntary jerky movements.

Resources for Huntingtons Disease

Blog Post: Somatic Instability and Huntington's Disease

This blog post provides a background to the role of somatic instability in the mutant Huntingtin (mHTT) gene in the development of Huntington's disease, and highlights the DNA repair process as a potential target for the development of new disease-modifying therapies.

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Literature for Huntington's Disease Research

Tocris offers the following scientific literature for Huntington's Disease Research to showcase our products. We invite you to request* or download your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.

Huntington's Disease Research Product Guide

Huntington's Disease Research Product Guide

This product guide provides a background to Huntington's disease research and lists around 100 products for the study of:

  • Somatic Instability
  • Proteolysis and Inclusion Bodies
  • Transcriptional Dysregulation
  • Mitochondrial Dysfunction
  • Nuclear-Cytoplasmic Transport Interference
  • Excitotoxicity
  • Stem Cells
Autophagy Scientific Review

Autophagy Scientific Review

Written by Patricia Boya and Patrice Codogno, this review summarizes the molecular mechanisms, physiology and pathology of autophagy. The role of autophagy in cell death and its links to disease are also discussed. Compounds available from Tocris are listed.

Stem Cells Scientific Review

Stem Cells Scientific Review

Written by Kirsty E. Clarke, Victoria B. Christie, Andy Whiting and Stefan A. Przyborski, this review provides an overview of the use of small molecules in the control of stem cell growth and differentiation. Key signaling pathways are highlighted, and the regulation of ES cell self-renewal and somatic cell reprogramming is discussed. Compounds available from Tocris are listed.

Huntington's Disease Poster

Huntington's Disease Poster

Huntington's disease (HD) is a severe monogenic neurodegenerative disorder, which is characterized by the prevalent loss of GABAergic medium spiny neurons (MSN) in the striatum. This poster summarizes the effects of mutant huntingtin aggregation implicated in the pathology of HD, as well as highlighting the use of iPSCs for HD modeling.