Understanding the Cellular Basis of Movement Disorders

Northwestern University At Chicago, Evanston IL

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder arising from an expanded polyglutamine tract in the transcriptional repressor ATAXIN1 (ATXN1). It exemplifies two perplexing features that characterize neurodegenerative diseases as a class: SCA1 appears in adulthood, even though caused by a mutation in a gene that is expressed from development onward, and SCA1 deterioration begins in a specific brain region (in this case, the cerebellum) before spreading to other areas. We have sought to understand both these features, and this competing renewal builds on our discoveries that transcriptional dysregulation occurs in SCA1 mice within the first two weeks of life, and cerebellar neurogenesis is altered by mutant ATXN1. Much is known about the later stages of SCA1, thanks in large part to mouse models that replicate the main features of the disease. The polyglutamine expansion renders ATXN1 resistant to normal degradation pathways, and cerebellar Purkinje cells, which are the first to succumb to the disease, seem unable to handle the excess protein. (It is thought that other brain regions are able to postpone degeneration by sequestering the protein into inclusions, which are notably absent in the Purkinje neurons.) We and others found that SCA1 mice, which start to have mild incoordination on the rotarod ~3 months of age, show transcriptional alterations early in life, including downregulation of the angiogenic and neurotrophic factor VEGF. We therefore examined early cerebellar development in more detail and demonstrated that expanded ATXN1 causes cerebellar stem cells to preferentially differentiate into GABAergic molecular layer inhibitory interneurons at the expense of astrocytes, resulting in heightened GABAergic inhibition of Purkinje cells. The links in the chain from early development to symptom onset, however, remain unclear, and we must understand this pathogenic evolution in order to find viable points of intervention, as recently done for another member of the polyglutamine family, Huntington's disease. We hypothesize that early developmental perturbations are necessary to set the stage for later degeneration. To test this hypothesis, we have developed new mouse models that enable us to control the timing of mutant ATXN1 expression. We will use these mice to learn if there are certain developmental windows that are crucial for later disease onset. We will also modulate processes such as cerebellar neurogenesis to determine whether these can postpone or prevent symptom onset.