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Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease

Nature Reviews Neuroscience volume 1, pages 109–115 (2000)Cite this article

Key Points

  • Polyglutamine disorders involve an expanded stretch of CAG trinucleotides that encodes a glutamine tract in proteins specific for each disease. The discovery of this similarity among very heterogenous disorders has pointed to a shared mechanism for the initiation of the pathogenesis, which is probably related to the ability of the mutant protein to undergo self-aggregation, forming insoluble cellular inclusions.

  • In every polyglutamine disorder, the phenotype caused by the mutant allele is dominant. In addition, each disease shows a characteristic threshold for polyglutamine length below which symptoms do not occur. Above the threshold, there is a progressive decrease in onset age with polyglutamine length.

  • The discovery of the glutamine tract as a crucial element in triggering the pathological changes has led to the development of several transgenic mouse models of the different disorders. They have been designed either to reproduce the disease phenotype by the introduction of the mutant version of the human gene or to reproduce the genotype by introducing an equivalent mutation into the endogenous locus.

  • Mice that express the polyglutamine fragments of human huntingtin tend to show cellular inclusions analogous to those described in Huntington's disease. However, these animals do not show the whole phenotypic characteristics of the human pathology as, for instance, cell death is not observed. In fact, for neuronal loss to occur, expression of the full-length mutant protein is necessary.

  • Mice that encode an enlarged glutamine tract in the endogenous huntingtin gene do not develop profound neurological signs and, similarly, the formation of cellular inclusions is subtle and progresses very slowly. Therefore, these animals may be valuable for investigating the mechanism of initiation of the disorder, but are not likely to illuminate its final stages.

  • The genetic analysis of the polyglutamine disorders indicates that the development of therapeutic strategies should focus on four main points: first, the study of the abnormal conformation of the expanded glutamine tract; second, the identification of the targets first affected by the mutant protein; third, the examination of the biochemical changes downstream from the initiating process; and last, the replacement of lost tissue through neuronal transplantation.

Abstract

Two decades ago, molecular genetic analysis provided a new approach for defining the roots of inherited disorders. This strategy has proved particularly powerful because, with only a description of the inheritance pattern, it can uncover previously unsuspected mechanisms of pathogenesis that are not implicated by known biological pathways or by the disease manifestations. Nowhere has the impact of molecular genetics been more evident than in the dominantly inherited neurodegenerative disorders, where eight unrelated diseases have been revealed to possess the same type of mutation — an expanded polyglutamine encoding sequence — affecting different genes.

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Figure 1: Relationship between age at onset and CAG repeat length for polyglutamine disorders.
Figure 2: The pathogenic process in polyglutamine disorders.

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Acknowledgements

The authors thank J.-P. Vonsattel for his contribution. Their work is supported by the Huntington's Disease Society of America Coallition for the Cure, the Hereditary Disease Foundation and NIH.

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  1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, 02129 , Massachusetts, USA

    James F. Gusella & Marcy E. MacDonald

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  1. James F. Gusella
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Glossary

SPINAL AND BULBAR MUSCULAR ATROPHY

Disorder characterized by progressive weakness and wasting of mouth, throat and skeletal muscles, which tends to affect only men.

POLYMORPHISM

The simultaneous existence in the same population of two or more forms (alleles) of a DNA sequence with a frequency that is greater than 1%.

MEDIUM SPINY NEURONS

Cell population that constitutes the main striatal inhibitory output to the globus pallidus.

SPINOCEREBELLAR ATAXIA

Disorder characterized by progressive cerebellar atrophy, which leads to gait ataxia and incoordination.

CHOREOATHETOSIS

Movement disorder characterized by constant writhing and jerking motion.

SDS–PAGE

Sodium dodecyl sulphate-polyacrylamide gel electrophoresis. A method for resolving a multimeric protein into its subunits and determining their separate molecular weights.

AMYLOID FIBRES

Insoluble, relatively inert fibres that are resistant to proteolysis, made from proteins in a β-pleated structure.

PROTEASOME

Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

YEAST ARTIFICIAL CHROMOSOME

A cloning vector capable of propagation in yeast, where it functions as an artificial chromosome.

CASPASES

Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues.

DOMINANT-NEGATIVE

A mutant protein that reduces the activity of the wild-type form.

MINOCYCLINE

An antibiotic that belongs to the tetracycline group.

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Gusella, J., MacDonald, M. Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1, 109–115 (2000). https://doi.org/10.1038/35039051

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