Research Fellowship Grant

Keyi Zhu, MD, PhD

Baylor College of Medicine
Identifying common genetic modifiers of Spinocerebellar ataxias (SCAs) using Drosophila model

Spinocerebellar ataxias (SCAs) are a group (~30) of heterogeneous neurodegenerative diseases that affect the cerebellum, brain stem, spinal cord and other parts of the central nervous system causing similar clinical symptoms and neuropathology. The irreversible and progressive conditions eventually lead to patients’ severe disability and death. Although mutations causing spinocerebellar ataxias have been discovered, we still know very little about how the diseases progress, and virtually nothing about how they can be prevented or treated. One possible approach to define therapeutic avenues is to ask what other genes might confer protection against spinocerebellar ataxias when their activities are altered. These genes (known as modifier genes) are mostly unknown and difficult to identify. To overcome this difficulty, I will use Drosophila (fruit fly) models of SCA1, SCA2 and SCA7 generated by introducing the human gene triggering the corresponding spinocerebellar ataxia into the Drosophila genome. These Drosophila models of disease will allow me to perform genome-wide screen for modifier genes that are not feasible using other animal models.

The modifier genes identified in this work will help us better understand the pathogenesis of spinocerebellar ataxias. More significantly, I expect that some of these modifier genes will encode ‘drugable’ proteins that may become therapeutic targets for SCA1, SCA2 and SCA7. I hope that these common therapeutic targets will be the first step towards benefiting patients with different spinocerebellar ataxias.