Grant: Operating Grant

Using chemicals to mutate their DNA, mice were derived that displayed seizures, tremor and an abnormal gait. On inspection, we discovered that these defects were associated with a single base pair change in the DNA that encodes a protein known as FRMD5. Very little is known about FRMD5, but it is thought to play an important role in function of the cell cytoskeleton; i.e., the scaffolding that supports cell shape and numerous internal signaling functions. Our analysis of the FRMD5 mutant mice suggests that the change in FRMD5 leads to the partial loss of special cells in the cerebellum, a major motor control area of the brain. This investigation is designed to expose the precise cellular mechanisms that are disrupted by this abnormal protein. These studies will identify critical pathways used by neurons for normal function and survival, providing deeper insight into the characteristics that serve to protect some neurons from death while making others susceptible. Our studies will also elucidate new mechanisms whereby cerebellar neurons develop functional connections and will delineate the extent to which FRMD5 mutation may also cause human cerebellar disease. This knowledge will deepen our understanding of the factors that can lead to cerebellar dysfunction and other debilitating neurological conditions that are particularly common in the aging population.