Psychosine induces the dephosphorylation of neurofilaments by deregulation of PP1 and PP2A phosphatases.

[krabbe disease]

Patients with Krabbe disease , a genetic demyelinating syndrome caused by deficiency of galactosyl-ceramidase and the resulting accumulation of galactosyl-sphingolipids , develop signs of a dying-back axonopathy compounded by a deficiency of large -caliber axons . Here , we show that axonal caliber in Twitcher mice , an animal model for Krabbe disease , is impaired in peripheral axons and is accompanied by a progressive reduction in the abundance and phosphorylation of the three neurofilament (NF ) subunits . These changes correlate with an increase in the density of NFs per cross-sectional area in numerous mutant peripheral axons and abnormal increases in the activity of two serine /threonine phosphatases (PP 1 and PP 2 A ) in mutant tissue . Similarly , acutely isolated mutant cortical neurons show abnormal phosphorylation of NFs . Psychosine , the neurotoxin accumulated in Krabbe disease , was sufficient to induce abnormal dephosphorylation of NF subunits in a normal motor neuron cell line as well as in acutely isolated normal cortical neurons . This in vitro effect was mediated by PP 1 and PP 2 A , which specifically dephosphorylated NFs . These results demonstrate that the reduced caliber observed in some axons in Krabbe disease involves abnormal dephosphorylation of NFs . We propose that a psychosine-driven pathogenic mechanism through deregulated phosphotransferase activities may be involved in this process .