Choline acetyltransferase: The structure, distribution and pathologic changes in the central nervous system

Abstract

Choline acetyltransferase (ChAT), the enzyme responsible for the biosynthesis of acetylcholine, is presently the most specific indicator for monitoring the functional state of cholinergic neurones in the central and peripheral nervous systems. ChAT is a single‐strand globular protein. The enzyme is synthesized in the perikaryon of cholinergic neurones and transported to the nerve terminals probably by both slow and rapid axoplasmic flows. ChAT exists in at least two forms in cholinergic nerve terminals: (i) soluble; and (ii) non‐ionically membrane‐bound forms. Multiple mRNA species of ChAT (R‐, N‐and M‐types) are transcribed from different promoter regions and produced by different splicing in the mouse, rat, and human. All transcripts encode the same ChAT protein in rodents, while in human M‐type mRNA has the capability to generate both large and small forms of ChAT proteins and R‐and N‐types ChAT mRNA generate a small form, which corresponds to the rodent ChAT. The genomic structure of ChAT is unique compared with other enzymes for neurotransmitters. The first intron of the ChAT gene encompasses the open reading frame encoding another protein, vesicular acetylcholine transporter (VAChT), which is responsible for the transportation of acetylcholine from the cytoplasm into the synaptic vesicles. The expressions of ChAT and VAChT appear to be coordinately regulated by multiple regulatory elements in cholinergic neurones. Immunohistochemical and in situ hybridization studies have revealed the localization of cholinergic neurones in the central nervous system: the medial septal nucleus, the nucleus of the diagonal band of Broca, the basal nucleus of Meynert, the caudate nucleus, the putamen, the nucleus accumbens, the pedunculopontine tegmental nucleus, the laterodorsal tegmental nucleus, the medial habenular nucleus, the parabigeminal nucleus, some cranial nerve nuclei, and the anterior horn of the spinal cord. Focally distributed cholinergic neurones project fibers to many areas in the central nervous system and construct a complicated cholinergic network, playing an important role in neuropsychic activities, such as learning, memory, arousal, sleep and movement. Central cholinergic neurones are involved in several neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis, in which disturbance of the central cholinergic system does not appear to be closely related to the etiology, but rather to the development of clinical symptoms. In addition, abnormalities of ChAT in the brain have been recently demonstrated in schizophrenia and sudden infant death syndrome.