Fig. 3

Neurotransmitter identity (adapted from ref. 232). Multiple transmitters and transmitter-like substances have been studied in PD and it is clear that neurons releasing neurotransmitters other than dopamine (DA) are also susceptible to neurodegeneration.²²⁷ These transmitters include the monoamines serotonin (5-HT) and noradrenaline (NA) and the neurotransmitters acetylcholine (ACh). In catecholaminergic neurons (dopaminergic, noradrenergic and adrenergic), the neurotransmitter is synthesised from the amino acid tyrosine (Tyr) in a common biosynthetic pathway.²³² Mesodiencephalic DN of the SNC, together with the noradrenergic neurons of the LC, require the expression of tyrosine hydroxylase (TH) and amino acid decarboxylase (DDC). As opposed to DN, noradrenergic populations further require the expression of dopamine beta-hydroxylase (DBH), which converts DA into noradrenaline. Adrenergic neurons, in turn, also require the expression of phenylethanolamine-N-methyl-transferase (PNMT), which converts noradrenaline into adrenaline. On the other hand, although serotonergic neurons from the raphe nucleus synthesise 5-HT through the hydroxylation of tryptophan, a reaction catalysed by tryptophan hydroxylase (TPH), they also require the expression of DDC.²³² In neurotransmitter packing, both catecholaminergic and serotonergic neurons require the same vesicular monoamine transporters, SLC18A1/2.²³² The transporter responsible for the re-uptake of neurotransmitters from the synaptic cleft is specific for each population. Serotonergic neurons require the transporter SLC6A4, DN require SLC6A3 and noradrenergic neurons require SLC6A2. For neurotransmitter degradation, the catecholaminergic neurons require catechol-O-methyl transferase (COMT), monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH), while the serotonergic neurons only require MAO and ALDH.²³² Cholinergic neurons secrete acetylcholine (ACh), which is synthesised by the choline acetyltransferase (CHAT) from acetyl-CoA and choline (Chol). In cholinergic neurons from the 10N, ACh is packed into synaptic vesicles by an energy-dependent process that involves the SLC18A3. This vesicular ACh is released in the synaptic cleft and is rapidly converted into Chol, by the acetylcholinesterase (ACHE), which then is transported intracellularly by SLC5A7.^{227, 233} (also see Supplementary 2)