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  • Review Article
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Experimental therapeutics in transgenic mouse models of Huntington's disease

Nature Reviews Neuroscience volume 5, pages 373–384 (2004)Cite this article

Key Points

  • Huntingtin is a predominantly cytoplasmic protein that is found in neurons throughout the brain. The precise mechanism by which mutant huntingtin causes Huntington's disease (HD) is unknown but seems to be gain-of-function. The gene that encodes this protein can be mutated by expansion of a trinucleotide CAG repeat that encodes glutamine.

  • N-terminal fragments of mutant huntingtin form toxic protein aggregates in neurons. Mutant huntingtin causes progressive neuronal dysfunction and death — HD is ultimately lethal.

  • There are several different transgenic mouse models of HD that have enhanced the study of this disorder and the capacity to test promising therapeutics. Mouse models fall into three categories: (1) those that express full-length mutant human huntingtin; (2) those that express fragments of the mutant human huntingtin gene; and (3) those with CAG repeats inserted into the murine huntingtin gene.

  • These mouse models have been used to investigate the role in HD of several processes that might be targeted therapeutically. These processes include: proteolysis of huntingtin; aggregation of huntingtin; apoptosis; transcriptional dysregulation; mitochondrial dysfunction; excitotoxicity; inflammation and oxidative damage; and transglutaminase activity.

  • Vaccination against toxic proteins and transplantation of healthy brain tissue are two approaches to treatment that are under investigation.

  • There is no consensus as to which type of mouse model is the best model of human HD. There have been few clinical trials of treatments in humans on which to base a comparative conclusion.

Abstract

Despite important advances in understanding and elucidating the molecular and mechanistic pathways that mediate progression in Huntington's disease (HD), effective pharmacotherapy remains elusive. Insights into disease pathogenesis have come from studies using tissue culture, yeast, Caenorhabditis elegans, Drosophila melanogaster and transgenic mouse models. Here, we present a brief overview of HD pathogenesis and discuss the efficacy of therapeutic agents in transgenic mouse models of HD. We conclude by considering issues that affect the translation of findings in transgenic mouse models of HD to human clinical trials.

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Figure 1: Downstream targets for therapeutics for Huntington's disease (HD).
Figure 2: Putative sites of cleavage of huntingtin (Htt) by caspases (Casp), calpains and aspartyl protease.
Figure 3: Sites of action of therapeutic compounds that modulate gene transcription.
Figure 4: Sites of action of mitochondrial toxins and therapeutic agents that modulate energy metabolism.

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Acknowledgements

The secretarial assistance of G. Strong and C. Boyd is gratefully acknowledged. H. Ryu is thanked for assistance in making the figures. This work is supported by the Huntington's Disease Society of America Coalition for the Cure, the Hereditary Disease Foundation, National Institutes of Health grants and the Veteran's Administration.

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Authors and Affiliations

  1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Room F610, 525 East 68th Street, New York, 10021, NY, USA

    M. Flint Beal

  2. Massachusetts and the Departments of Neurology, Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, Pathology and Psychiatry, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Robert J. Ferrante

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DATABASES

Entrez Gene

BDNF

caspase 1

caspase 2

caspase 3

caspase 6

caspase 8

CBP

Crx

DRPLA

HD

Hdh

Ncor1

Pqbp1

Sca1

SCA3

Sca7

SP1

OMIM

Alzheimer disease

amyotrophic lateral sclerosis

Huntington disease

FURTHER INFORMATION

Beal's homepage

HD Base

Glossary

CHOREIFORM MOVEMENT DISORDER

An involuntary spasmodic twitching or jerking in groups of muscles that is not associated with the production of definite purposeful movements.

DYSTONIA

Disordered tonicity of muscle.

UBIQUITINATED

Refers to the addition of ubiquitin to a damaged protein, tagging it for degradation by the proteasome.

CHAPERONE

Cytoplasmic proteins that bind to nascent or unfolded polypeptides and ensure correct folding or transport.

CONDITIONAL MUTATION

Mutations that generate an observable mutant phenotype under a given set of growth conditions (restrictive conditions), but no mutant phenotype (or a reduced phenotype) under a separate set of conditions (permissive conditions).

YEAST ARTIFICIAL CHROMOSOME

(YAC). A specialized vector for cloning large pieces of DNA. It contains a centromere, an autonomously replicating sequence, a pair of telomeres, selectable marker genes and the DNA fragment to be cloned.

HYPOKINESIS

Diminished or slow movement.

MINOCYCLINE

A semisynthetic antibiotic that is effective against tetracycline-resistant staphylococcus infections.

MITOCHONDRIAL PERMEABILITY TRANSITION

(MPT). A nonspecific increase in the permeability of the inner mitochondrial membrane that occurs when matrix calcium is greatly increased, especially under oxidative stress and adenine nucleotide depletion. MPT is associated with the opening of a nonspecific pore in the mitochondrial inner membrane, which transports molecules that are smaller than 1,500 Daltons.

TUNEL TECHNIQUE

This technique enables the visualization of cells undergoing apoptosis by labelling the broken ends of the double-stranded DNA with biotin-conjugated dUTP, using the enzyme terminal deoxynucleotidyl transferase.

HISTONES

A family of small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells, that associate with DNA to form a nucleosome.

ACONITASE

A key enzyme in the citric acid cycle. It is particularly susceptible to free radical damage owing to its iron–sulfur cluster.

FREE RADICAL SPIN TRAP

A series of nitrone compounds that react with free radicals such as superoxide to generate more stable adducts.

CYCLOOXYGENASE

An enzyme protein complex present in most tissues that catalyses two steps in prostaglandin biosynthesis. It produces prostaglandins and thromboxanes from arachidonic acid.

ENCEPHALITIS

Inflammation of the brain.

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Beal, M., Ferrante, R. Experimental therapeutics in transgenic mouse models of Huntington's disease. Nat Rev Neurosci 5, 373–384 (2004). https://doi.org/10.1038/nrn1386

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