Responses to cyclic AMP is impaired in the twitcher Schwann cells in vitro

Twitcher (twi/twi) is a murine model of genetic demyelinating disease globoid cell leukodystrophy (GLD). Available data suggest that demyelination in GLD is caused by degeneration or dysfunction of myelin-forming cells resulting from an accumulation of psychosine, a toxic substrate of galactosylceramidase and a potent inhibitor of protein kinase C (PKC). We investigated proliferation and differentiation of twi/twi Schwann cells in response to forskolin, an adenylate cyclase activator. In twi/twi Schwann cells isolated at the postnatal day (P) 10 prior to the onset of demyelination, proliferation and an expression of the surface galactocerebroside (galC) in response to forskolin were similar to those of +/+ mice. However, in twi/twi Schwann cells isolated from demyelinating sciatic nerves at P20 or P30, fewer numbers of cells expressed surface galC compared to age matched control (+/+) Schwann cells. In all Schwann cells, surface galC expression was lost after 3 days in vitro (DIV). However, with an administration of 50 microM forskolin in the media containing 1% fetal bovine serum (FBS) on the 4 DIV, surface galC could be reexpressed in all +/+ and P10 twi/twi Schwann cells but not in P20 or P30 twi/twi cells. In the media containing 10% FBS, forskolin also stimulated proliferation of Schwann cells from P10 twi/twi, and P10 and P30+/+ mice but not those from P30 twi/twi mice. These results are consistent with a metabolic perturbation of twi/twi Schwann cells that may be reflecting cellular dysfunctions by inhibition of the PKC.