Young Investigator Research Grant

Vikram G. Shakkottai, MD, PhD

University of Michigan Medical Center, Ann Arbor, Michigan
Understanding the role of altered physiology in the pathogenesis of SCA3

Spinocerebellar ataxia type 3 (SCA3), a disease that leads to progressive loss of coordination of movement, is caused by the abnormal folding of the disease protein, ataxin-3. SCA3 is probably the most common dominantly inherited ataxia in the world. Although loss of nerve cells in the brain is the end-result of SCA3 and related protein folding disorders, recent studies have revealed that changes in electrical properties of nerve cells precede the loss of these cells in animal models of disease. In our laboratory, studies of genetically modified mice have shown overt changes in their motor behavior without evidence of prominent loss of nerve cells. The proposed studies spring from research demonstrating that in mouse models of disease, alterations in electrical properties of nerve cells in the cerebellum (the part of the brain responsible for coordination of movement and affected in SCA3) can cause profound motor symptoms even in the absence of overt loss of nerve cells. The study proposes to look for changes in electrical properties of nerve cells in the cerebellum in a mouse genetically modified to resemble human SCA3. In preliminary data we demonstrate that nerve cells in the cerebellum have early changes in their electrical properties that may be amenable to pharmacologic correction. Identifying abnormalities in the electrical properties of nerve cells may provide ways to develop new drugs to treat this disorder.