Variation in key human cholinergic genes-relationship to CNS disorders

Impaired cholinergic neurotransmission is involved in diverse CNS disorders including Alzheimer's disease, post-traumatic stress disorder, and depression. Variations in several key genes associated with cholinergic neurotransmission, as well as inherited susceptibility to traumatic life events and xenobiotic insults, may variously be implicated with causing genetic predisposition for CNS disorders affecting the cholinergic network. The relevant genes include the neuronal nicotinic and muscarinic acetylcholine receptor genes as well as the cholinesterase genes encoding the acetylcholine hydrolyzing enzymes acetylcholinesterase and butyrylcholinesterase (AChE, BuChE). For example, the biochemically deficient K variant of the BuChE protein has recently been reported to increase the risk associated with apolipoprotein E4 for late onset neuropathologies. In addition, carriers of biochemically deficient BuChE variants suffer extreme sensitivity to drugs affecting cholinergic neurotransmission, such as cholinesterase inhibitors. We have recently found that exposure to such drugs may promote cholinergic hyperexcitation and facilitate initiation of a transcriptional feedback loop resulting in AChE accumulation. Similar processes take place under acute psychological stress, which implies that individuals with inheritable sensitivity to stressful events (due to polymorphisms in other genes) may be subject to parallel feedback responses. In view of the finding that transgenic excess of AChE promotes neurodeteriorative processes, these observations suggest that both genetic and epigenetic variabilities affecting the activity of key cholinergic genes and their protein products represent important risk factors that can determine susceptibility to cholinergic CNS disorders.