Research Grant Award

Yuanxin Hu, PhD

The University of Chicago
The role of P/Q calcium channel fragments in SCA 6 pathogenesis

Calcium channels are specialized proteins that allow calcium or other ions to cross nerve cell membranes. They are necessary for normal functions in the brain. Many brain disorders result from the dysfunction of these channels. Neurodegenerative diseases in which ion channel dysfunction plays a role include Parkinson's disease, the familial hemiplegics migraine, episodic ataxia type 2 (EA 2) , and spinocerebellar ataxia type 6 (SCA6). The last of these diseases is caused by dysfunction of P/Q-type Ca2+ channel protein. All proteins are made of chains of different amino acids. SCA 6 is caused by a mutation that increases in the numbers of the amino-acid glutamine in the part of the amino acid chain forming the tail (called the C-terminus) of the main channel protein subunit of the P/Q-type Ca2+ channel (called the alpha 1A subunit). The result of this expansion is Purkinje cell death. Our resent data shows that the tail (C terminus) of the 1A subunit protein is cleaved (chopped off) in the cell, possible by one of a class of enzymes called proteases. After cleavage the C-terminus tail contains the mutant polyglutamine expansion and localities to the nucleus, it causes cell death. In this study we hope to use cellular and animal models to understand how and why the cleavage and translocation happen and how this causes SCA 6.