Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders that result from degeneration of corticospinal tract axons. Patients commonly present with spasticity in the lower limbs, as the longest nerve fibers appear to be the earliest affected. Patients with the complicated form of HSP may also present with retinopathy, ataxia, peripheral polyneuropathy, and cognitive deficit. To date, 57 distinct chromosomal HSP loci have been identified through genetic linkage analysis of affected families. Of particular interest to this study is the finding that an autosomal dominant form of HSP (AD-HSP) is caused by mutations in the Kif5A gene, a kinesin transport motor enriched in neurons. In addition, approximately 10% of the known cases of complicated HSP are due to mutations in Kif5A. Clinical treatment for HSP is presently limited to symptomatic reduction of muscle spasticity. While this can be effective for short periods, progressive axonal degeneration leads to poor long-term prognoses. As a result, there is a need for a more mechanistic understanding of the primary causes of HSPs. This proposal is targeted at broadening our understanding of the physiological manifestation of AD-HSP-causing mutations in Kif5A. With this goal in mind, we will pursue two lines of experimentation. First, we will continue our in vitro studies to measure the altered catalytic and mechanical properties of Kif5A with AD-HSP-causing mutations. Second, we will identify Kif5A cargoes in neurons and examine the kinetics of cargo transport in vivo in the presence of wild-type and mutant Kif5A. Our long-term goal is a mechanistic understanding of how mutations in the Kif5A gene alter its normal cellular functions so that ultimately therapies can be designed to treat the fundamental cause of AD- HSP, rather than attempting to treat the physiological manifestation of the underlying dysfunction. In addition, the centrality of kinesin-dependent transport in a host of cellular functions gives the opportunity for outcomes of this study to have far-reaching potential in therapies for other human disorders.