A new mouse model of a CAG repeat disorder supports the hypothesis that soluble mutant proteins might be more dangerous than aggregates in some neurodegenerative diseases. As with Alzheimer's and Parkinson's, the CAG repeat disorders result in mutant proteins that aggregate abnormally. The mutations result in the expansion of a CAG trinucleotide encoding glutamine. Huntington's disease is the best known, but at least eight other inherited neurodegenerative disorders are linked to expanded proteins with CAG repeats.

In spinocerebellar ataxia type 1 (SCA1), mutant ataxin-1 protein expanded by CAG repeats collects in intracellular aggregates called nuclear inclusions, primarily in neurons of the cerebellum, brain stem, and spinal cord. Transgenic mouse models expressing the mutant ataxin-1 protein have shed light on some aspects of the disease process, but they have not replicated the early death of the human disease, nor have they explained why a protein mutation that is widely distributed affects only certain neuronal populations.

To address the latter question, Huda Zoghbi and colleagues at the Baylor College of Medicine in Houston, Texas, and other institutions, decided to "knock" the mutation into the mouse protein, rather than introduce the human protein. By creating more "normal" temporal and spatial expression patterns at endogenous levels, the researchers hoped to reproduce the motor and cognitive deficits and early death seen in human SCA1 patients.

In an earlier paper (Lorenzetti et al., 2000), the group reported knocking in a 78 CAG repeat, which generated a disease-appropriate expression pattern of ataxin-1. However, the mouse's short lifespan apparently precluded the development of serious disease manifestations, especially the cognitive deficits seen later in the human disease. In this report, the authors knocked in a longer, 154 CAG repeat to accelerate the disease process and produce a disorder that closely resembles human SCA1.

This model progresses slowly, invariably involving muscle wasting, weight loss, and an early death. At 5 weeks of age the mice show evidence of ataxia, and by 7-9 weeks they display memory loss accompanied by electrophysiological evidence of altered LTP in hippocampal slice preparations.

The brain areas most vulnerable to neurodegeneration contained the highest levels of soluble mutant protein. In particular, in the Purkinje cells of the cerebellum, which are most affected in human disease, ataxin-1 aggregates did not form until very late. By contrast, aggregates were more prevalent and formed early in cerebral cortical and hippocampal pyramidal neurons, which do not degenerate in significant numbers in the human disease.

The authors suggest a disease process wherein soluble ataxin-1 is toxic to neurons, and those cells best able to sequester the mutant protein into aggregates survive the longest. This hypothesis, write the authors, is consistent with evidence from both AD and PD. They cite evidence that the soluble form of Aβ, not the Aβ in plaques, correlates best with neurodegeneration in AD (McLean et al., 1999), and that it is the soluble Aβ that impairs hippocampal synaptic plasticity (see related news item.)

This study leaves open the question how soluble CAG-expanded proteins leads to neurodegeneration. One idea the authors could pursue with their current strain of knockin mice is that mutant ataxin-1 might disrupt normal gene expression patterns, perhaps because its extra glutamines interfere with the normal binding between the transcriptional activators Sp1 and other components of the transcriptional machinery, such as TAFIID. Dimitri Krainc and his colleagues recently demonstrated such an interaction for mutant huntingtin (see related news item), and in this week's Science, Robert Tijan at the University of California, Berkeley, expands on the emerging connection between polyglutamine tracts and transcription factors in a Perspectives article.—Hakon Heimer


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News Citations

  1. Earliest Amyloid Aggregates Fingered As Culprits, Disrupt Synapse Function in Rats
  2. Transcriptional Activators Kidnapped by Huntingtin

External Citations

  1. Lorenzetti et al., 2000
  2. McLean et al., 1999

Further Reading

Primary Papers

  1. . A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron. 2002 Jun 13;34(6):905-19. PubMed.