Dopamine synthesis and transport: current and novel therapeutics for parkinsonisms

Abstract

Parkinsonism is the primary type of movement disorder in adults, encompassing a set of clinical symptoms, including rigidity, tremors, dystonia, bradykinesia, and postural instability. These symptoms are primarily caused by a deficiency in dopamine (DA), an essential neurotransmitter in the brain. Currently, the DA precursor levodopa (synthetic L-DOPA) is the standard medication to treat DA deficiency, but it only addresses symptoms rather than provides a cure. In this review, we provide an overview of disorders associated with DA dysregulation and deficiency, particularly Parkinson's disease and rare inherited disorders leading predominantly to dystonia and/or parkinsonism, even in childhood. Although levodopa is relatively effective for the management of motor dysfunctions, it is less effective for severe forms of parkinsonism and is also associated with side effects and a loss of efficacy over time. We present ongoing efforts to reinforce the effect of levodopa and to develop innovative therapies that target the underlying pathogenic mechanisms affecting DA synthesis and transport, increasing neurotransmission through disease-modifying approaches, such as cell-based therapies, nucleic acid- and protein-based biologics, and small molecules.

Keywords: Parkinson's disease; dopamine deficiencies; inherited disorders; parkinsonism; small molecules; therapy.

Figure 1.. Simplified overview of the pathways involved in the biosynthesis, metabolism and transport of DA, highlighting the targets of current therapeutic approaches designed to enhance DA signaling.

DA is synthesized by PAH, TH and AADC, and is then packed into synaptic vesicles by VMAT2 and released into the synapse for binding to receptors on the postsynaptic neuron. Residual DA in the synaptic cleft undergoes reuptake by DAT and is repackaged in synaptic vesicles or metabolized by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetic acid (DOPAC), which can be exported to astrocytes and microglia for further metabolism (see Meiser et al. [18] and Winner et al. [17]). See also Meiser et al. [18] for further reading on an alternative DA biosynthesis pathway. Current treatments for DA deficiencies that boost DA signaling involve administration of levodopa, inhibitors of AADC, COMT and/or MAO-B, BH₄ (in BH₄-deficiencies) and DA agonists. Abbreviations: 3-OMD, 3-O-methyldopa; 4a-OH-BH₄, pterin-4-alpha-carbinolamine; 6-PTP, 6-pyruvoyl tetrahydropterin; AADC, aromatic acid decarboxylase; BH₄, (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin; COMT, catechol-O-methyltransferase; DAT, dopamine transporter; DHNTP, 7,8-dihydroneopterin triphosphate; DHPR, dihydropteridine reductase; DOPAC, 3,4-dihydroxyphenylacetic acid; GTPCH1, GTP cyclohydrolase; GTP, guanosine triphosphate; L-DOPA, L-3,4-dihydroxyphenylalanine; MAO-B, monoamine oxidase B; PAH, phenylalanine hydroxylase; PCD, pterin-4-alpha-carbinolamine dehydratase; PTPS, 6-pyruvoyl tetrahydropterin synthase; qBH2, dihydrobiopterin quinoid; SR, sepiapterin reductase; TH, tyrosine hydroxylase; VMAT2, vesicular monoamine transporter 2.

Figure 2.. Overview of novel therapies that aim to increase DA synthesis and signaling, focusing on cell-, nucleic acid-, and protein-based strategies, and small molecules.

Cell-based strategies aim to increase DA by replenishing DA producing neurons in patients with neurodegeneration. These cells can either be derived from established cell lines or from the patients themselves. Nucleic acid-based strategies on the other hand, aim to increase wildtype proteins by delivering genes to compensate for deficient proteins, by using RNA to stabilize protein targets or by editing variants in parkinsonisms with genetic etiology. Protein-based strategies aim to increase the levels of deficient proteins, and peptides can also act as carriers to deliver DA. Lastly, small molecule compounds can impart general neuroprotective effects, or stabilize or modulate the activity of specific proteins involved in DA signaling.