Provided are compositions and methods for the treatment of Krabbe and other neurodegenerative diseases associated with psychosine (and/or other storage material)—mediated axonal degeneration. Compositions and methods employ one or more inhibitor(s) of (1) a phosphotransferase activity of one or more kinase(s) such as CDK5, P38, jnk, src, CK2, PKC, GSK3α and β (2) a phosphotransferase activity of one or more phosphatase(s) such as PP1 and PP2 (3) a caspase/calpain activity of one or more caspases such as caspase 3 and calpains such as calpain 1 and 2 and/or (4) a sodium/calcium exchange protein such as NCX1. Inhibitors include small molecules (e.g., the GSK3β inhibitor L803 and the NCX1 inhibitor flecainide) and siRNA molecules that downmodulate cellular levels of one or more mRNA, such as PP1 mRNA. Inhibitors disclosed can cross the blood-brain barrier and, thus, are available to the CNS and effective in reducing psychosine-mediated axonal degeneration.
