Perturbation of protein kinase C subtype activation in X-ALD fibroblasts: possible involvement of protein kinase C in the pathogenesis of adrenoleukodystrophy.

Abstract

X-linked adrenoleukodystrophy (X-ALD; McKusick 300100) is an inborn error of metabolism affecting primarily the central nervous system white matter, adrenals and testes (Moser and Smith 1997). The prominent neuropathological feature of all patients with rapidly progressive cerebral forms of X-ALD is areas of demyelination and perivascular infiltration with round cells, which is indicative of an inflammatory process (Moser and Smith 1997). Biochemically, accumulation of very long-chain fatty acids is the hallmark of all forms of X-ALD (Moser and Smith 1997). However, the pathogenetic mechanisms linking the accumulation of very long-chain fatty acids and the inflammatory process and demyelination in the CNS are not known. We hypothesized that perturbation of protein kinase C (PKC) activation might represent the missing functional link between accumulation of VLCFA and perturbation of cellular function in X-ALD. PKC is a family of at least 11 enzymes that play a pivotal role in the lipid-mediated signal transduction pathway and have been implicated in the regulation of a large number of short- and long-term intracellular processes (Nishizuka 1989, 1992). The hypothesis that perturbation of PKC activation may play a significant role in the pathogenesis of X-ALD stems from several findings. (1) Several PKC subtypes, namely α, βI, βII y, e, and ζ, have been shown to be activated by cis-unsaturated fatty acids (Nishizuka 1989, 1992). (2) Myelin basic protein, one of the five main components of myelin in the CNS, is a PKC substrate (Nishizuka 1986). (3) PKC has been shown to play a significant role in the induction of inflammatory mediators in various tissues, including the CNS (Boneh et al 1993; Brenner et al 1992; Hartung and Toyka 1987; Jeremy et al 1987). As a first step towards elucidating the role of PKC in the induction of genes involved in the inflammatory reaction in X-ALD, we studied the translocation of PKC subtypes to the nucleus in X-ALD fibroblasts following phorbol ester activation.