Neural development and neurodegeneration: two faces of Neuropathy Target Esterase

Abstract

Neuropathy target esterase (NTE) is an integral membrane protein in vertebrate neurons. Recent evidence suggests that NTE plays an important role in neural development, possibly via involvement in a signalling pathway between neurons and glial cells. NTE is a member of a novel protein family, represented in organisms from bacteria to man. NTE comprises an N-terminal regulatory domain (with some sequence similarity to cyclic nucleotide-binding proteins) and a C-terminal catalytic domain: the latter has three predicted transmembrane segments and requires membrane-association for activity. In vitro, NTE potently catalyses hydrolysis of phenyl valerate: however, its physiological substrate is likely to be a metabolite of a much longer chain carboxylic acid, possibly associated with cell membranes. NTE was discovered originally as the primary target for those organophosphorus esters (OPs) which cause a delayed neuropathy with degeneration of long axons in peripheral nerves and spinal cord. Paradoxically, NTE’s catalytic activity appears redundant in adult vertebrates. Neuropathic OPs react covalently with NTE in a rapid two-step process which not only inhibits catalytic activity but also leaves a negatively-charged OP group attached to the active site serine. The latter event is proposed to induce a toxic gain of function in NTE. OP-modified NTE somehow engenders a “chemical transection of the axon”. In turn, this leads to calcium entry, elevation of axonal calpain activity and Wallerian-type degeneration. The net damage to peripheral nerve axons is a balance between ongoing degenerative and repair processes: the latter involve serine hydrolases which can be inhibited by the same OPs used to modify NTE.