Research Grant Award

Sian D Spacey, MD

University of British Columbia
The Role of the human P/Q Type Calcium Channel in the Pathogenesis of Ataxia

There are many causes of ataxia and yet the end result is a pathological involvement of the cerebellum. There are currently no treatments for cerebellar ataxia. In order to develop treatment it is important to understand the pathogenic mechanisms which lead to cerebellar ataxia. The hereditary ataxias are a good mode for studying pathological processes. We propose to study Episodic Ataxia type 2 (EA 2) a hereditary form of ataxia which results from mutations in the CACNA1A gene which codes for the Cav2.1 subunit of the P/Q type calcium channel.

The H1736L missense mutation in the CACNA1A genen causes pure cerebellar symptoms and cerebellar pathology. The mutated P/Q-type Ca channel is expressed widely throughout the brain, yet only cerebellar symptoms develop. We intend to investigate how a widely expressed mutation would result in isolated clinical pathology. We hypothesize that although the P/Q channel is expressed thoughout the brain, there are normal variants of the channel (splice variants) which are differentially expressed in different regions of the brain. In this study we will determine the relative expression levels of splice variants in different areas fo the brain. Furthermore, we hypothesize that interactions between these variants and mutations will influence the channel function (biophysical properties). In this study we will assess the biophysical properties of naturally-occurring P/Q-Type Ca channel mutants when expressed in different isoforms of Cav2.1. Specific splice variants may enhance or negate the effects of any given point mutation. Moreover, a mutation in one splice variant may yield a phenotype that is significantly different that the same mutation in another variant. This may account for the localized CNS pathology.

This research will further elucidate the pathophysiological mechanism involved in EA2. Insight into the cerebellar specific pathology associated with the widely expressed CACANA1A mutations will have application to understanding cerebellar ataxia in general and ultimately directed us towards treatment of ataxia.