Provided are compositions and methods for the treatment of Krabbe and other neurodegenerative diseases, including storage diseases such as GM1
gangliosidosis, Niemann-Pick
disease, Tay-Sachs
disease, Sandhoff
disease, metachromatic leukodystrophy, Canavan disease, Pelizaeus-Merzbacher disease, and storage conditions facilitated by aging of lysosomal functions, which are associated with psychosine (and / or other
storage material)-mediated axonal degeneration. Compositions and methods employ (1) one or more inhibitor of a phos-photransferase activity of one or more
kinase(s) such as, for example, CDK5, P38, jnk, src, CK2, PKC, GSK3α and β; (2) one or more inhibitor of a
phosphotransferase activity of one or more
phosphatase(s) such as, for example, the Ser / Thr
protein phosphatase PP1 and Tyr
protein phosphatase PP2; one or more inhibitor of a
caspase /
calpain activity of one or more caspases such as
caspase 3 and calpains such as
calpain 1 and 2; and (4) one or more inhibitor of a
sodium /
calcium exchange
protein such as, for example, NCX1. Inhibitors include small molecules, including the GSK3β inhibitor L803 and the NCX1 inhibitor flecainide, and siRNA molecules that downmodulate cellular levels of one or more mRNA, including siRNA that are capable of downmodulating the cellular expression of PP1. Inhibitors disclosed can cross the blood-brain barrier and, thus, are available to the
central nervous system (CNS) and effective in reducing psychosine-mediated axonal degeneration.