Abstract: Impaired axonal development and degeneration underlie many debilitating diseases, including hereditary spastic paraplegia (HSP). HSPs are a heterogeneous group of neurogenetic disorders characterized by axonopathy of cortical motor neurons (Fink, 2006; Blackstone et al., 2010). The axonal degeneration of these cortical projection neurons (PNs) in HSP patients disrupts the signals from brain to spinal motor neurons, leading to muscle weakness and spasticity. Since the discovery of the first HSP gene (SPAST) in 1999, over 80 distinct genetic loci associated with HSP have been identified. How the mutations of these divergent genes specifically result in axonal degeneration of cortical PNs remains largely unclear, which contributes to the lack of effective treatment to ameliorate, stop, or reverse axonal defects in HSPs.