Research Grant Award

Cornelius F. Boerkoel III

Baylor College of Medicine
Development of a mouse model for spinocerebellar ataxia with neuropathy

Spinocerebellar ataxia with neuropathy (SCAN1) is an inherited ataxia. As a consequence of the brain degeneration (cerebellar atrophy), patients are unable to walk and confined to a wheel chair by late adolescence to early adulthood. We have characterized the clinical features of this disease and have identi1ied the genetic cause as mutations in the gene tyrosyl-DNA phosphodiesterase (TDP1), a DNA repair enzyme. We now desire to turn our attention to understanding the function ofTOP1 in neural development, maintenance, and disease. To this end, we propose 1) to determine whether other DNA repair pathways that could compensate for the deficiency of TDP1 are expressed in the affected neurons, 2) to identify the proteins that TDP 1 associates with in order to obtain insights into the pathways that TDP 1 functions in, and 3) to generate a mouse model of SCAN 1 so that we can study the pathophysiology of this disorder in an animal model. Many diseases of DNA repair cause ataxia and other neurological problems; however, the reason that these disorders cause such severe neurological problems remains relatively undefined. Interestingly, TOP1 and many other DNA repair enzymes are highly expressed in the developing and mature central and peripheral nervous systems. These fascinating results suggest that TOP1 is involved in the development and maintenance of the nervous system as well as in generalized ONA repair. This proposal is an opportunity to define the role of one DNA repair enzyme in the development and maintenance of the nervous system and possibly provide insight into the neurological pathology of other sporadic ataxias and disorders of DNA repair. It is also an opportunity to generate a model system that will allow us to test potential treatments for SCAN1.