Defects in axon transport may initiate or exacerbate several neurodegenerative disorders. The long-term goal of this study is to determine if Lis1 regulates dynein activity and axon transport. Mutations in Lis1 cause classical lissencephaly, a developmental brain abnormality characterized by defects in neuronal positioning. Over the last decade, a clear link has been forged between Lis1 and the microtubule motor cytoplasmic dynein. Substantial evidence indicates that Lis1 functions in a highly conserved pathway with dynein to regulate neuronal migration and other motile events. Dynein-based retrograde transport is important for the survival and function of neurons, connecting target regions to neuronal cell bodies and nuclei. Lis1 interacts directly with dynein, but the mechanistic significance of this interaction is not well understood.
Aim 1 of this study proposes to examine the importance of Lis1 sub-domains on dynein interaction and stimulation using in vitro binding and ATPase assays.
Aim 2 will address whether Lis1 perturbations will affect retrograde transport in axons using time-lapse microscopy to track movements of labeled organelles. ? ? ?
