Some of the earliest cellular changes of the trinucleotide repeat disorder spinocerebellar ataxia type 1 (SCA1) appear only one day after the mutant gene that causes the disorder begins to be expressed. In a report in the February issue of Nature Neuroscience, Huda Zoghbi, Harry Orr, and their colleagues identify some of the transcripts that are up-, or down-regulated, long before pathologic changes are seen in their mouse model of the neurodegenerative disease.

SCA1, like the better known Huntington's disease, is caused by a mutation in a trinucleotide repeat that encodes polyglutamine. In the case of SCA1, the mutation is in a gene called ataxin-1, whose protein product has no known function, but is found throughout brain and other tissues. The authors have previously used their transgenic mouse model to show that the abnormal ataxin-1 does its damage in the nuclei of Purkinje cells in the cerebellum (as well as in other brain areas).

In the present paper they identified seven genes that are up- or downregulated after expression of the ataxin-1 gene begins. One was downregulated as early as one day after expression of the transgene commenced. The authors then found that expression of three of these gene products (measured by mRNA activity) were altered in human postmortem cerebellar tissue.

Understanding the earliest changes in neurodegenerative diseases may prove to be the most productive route for therapy, opine Robert Nussbaum and Georg Auberger of the National Genome Research Institute in a News and Views letter in the same issue. They suggest that other options, such as understanding how cells ultimately die or exploring ways to regenerate nervous system tissue may prove to be less fruitful.—Hakon Heimer


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Further Reading


  1. . Neurodegeneration in the polyglutamine diseases: Act 1, Scene 1. Nat Neurosci. 2000 Feb;3(2):103-4. PubMed.

Primary Papers

  1. . Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci. 2000 Feb;3(2):157-63. PubMed.