Abstract: Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia (HSP), a genettcally and clinically diverse group of disorders characterized by spasttcity and weakness of the lower extremities. HSP is one significant cause of chronic neurodisability due to the lack of effecttve treatments and a wide range of onset ages from early childhood to 70 years. These disorders are caused by axonal degeneration of cortical projection neurons, which disrupts the transmission of signals from these neurons to spinal motor neurons and muscles (Blackstone et al., 2011). Since the discovery of the first HSP gene (SPAST) in 1999, over 80 disttnct genettc loci associated with HSP have been identtffed. How the mutations of these functionally divergent genes speciffcally result in axonal degeneratton of corttcal projectton neurons remains largely unclear.