Research Fellowship Grant

Xiaofei Du, MD

The University of Chicago
Regulation of neuronal genes by the alpha1A C terminus of Calcium channel and disruption in SCA6

Spinocerebellar ataxia type 6 (SCA6) is form of autosomal dominant spinocerebellar ataxia characterized by slowly progressive incoordination of gait and poor coordination of hands, speech, and eye movements beginning after age 40. SCA6 is due to abnormal expansions of a trinucleotide CAG repeat encoding polyglutamine (polyQ) in the C terminus of the main pore-forming subunit alpha1A of a calcium channel protein that is highly expressed in nerve cells. Alpha1A subunits bearing the normal range of polyQ can be physiologically cleaved at the tail (C terminus) end to yield a free C terminus (alpha1ACT) that is normally transported into the nuclei of cerebellar Purkinje cells. This suggests that alpha1ACT is an important gene expression mediator.

Interestingly, we also observed that alpha1ACT with the normal range polyQ can enhance the neurite outgrowth in nerve-like cell line called PC12 cells, but the effect of the alpha1ACT on neurite outgrowth is lost in alpha1ACT bearing the SCA6 mutation, Q33. Take together, I am proposing that alpha1ACT, as a natural mediator of gene expression, enters the nucleus, binds to sites in target genes that control their expression region and thereby is involved in development and viability of Purkinje cells. Further I propose that in the SCA6 polyQ-expanded alpha1ACT this normal function is lost or altered.

To address these issues, I will use molecular approaches to characterize the role of normal and SCA6-derived alpha1ACT on gene expression and neuronal differentiation as a gene expression mediator. In addition, I plan to assess target gene expression profiles between alpha1ACT with normal range polyQ and SCA6 polyQ expansion in alpha1ACT transgenic mouse model. Other molecules involved with alpha1ACT-mediated gene expression will also be identified. In this way, I will be to able to sort out the relationship of these events, thereby obtaining important insights into potential causative mechanisms that may have relevance to SCA6.

Significance: If successful, this project will provide important insights into the physiological function of alpha1ACT and cause of SCA6. The roles of alpha1ACT with normal range polyQ and SCA6 polyQ expansion will be examined in gene expression regulation in alpha1ACT transgenic mice. I anticipate that certain target genes profiles or interacting proteins will be associated with the development of SCA6. This information will be important in directing our efforts in developing strategies to specifically target the pathogenic mechanism of SCA6. In this way, we can prevent and treat SCA6 more effectively.