Neurodegenerative Diseases

Hargreaves AJ, Alan J. Hargreaves

Organophosphorous compounds (OPs) are widely used in agriculture, industry and the home. Though best known for their acute effects when used as pesticides, which target acetylcholinesterase (AChE) activity in neuromuscular junctions and the central nervous system, not all OPs are potent inhibitors of this enzyme. The widespread use of OPs has heightened concern regarding their toxicity in man, with numerous reports linking OPs to various forms of delayed neuropathy encompassing a range of neurodegenerative, psychological and neurobehavioral effects. There is mounting evidence to suggest that sub-acute levels of OPs have the ability to interact directly with a range of target proteins in addition to AChE (i.e., noncholinergic targets), causing major disruption of membrane and protein turnover, protein phosphorylation, mitochondrial dysfunction, oxidative stress and cytoskeletal re-organisation, although the mechanisms involved are not fully understood. However, major advances have been made in the study of one OP binding protein neuropathy target esterase (NTE) in terms of its true physiological role. Additionally, there is increasing evidence for the ability of OPs to cause disruption in a number of metabolic and cell signalling pathways that affect neuronal cell proliferation, differentiation and survival and to interact direct with non-esterase proteins such as tubulin. The aim of this chapter is to review our current understanding of delayed neurotoxicity, to discuss how these molecular events may relate to each other and to suggest possible future directions in mechanistic studies of OP toxicity.