Dopamine: From Parkinson’s to Parkinsonism
By Tom Brock, Ph.D. From Cayman Chemical
In this Era of Aging, Parkinson’s Disease (PD) is becoming more common. In patients with PD, muscle movement declines inexorably from tremors to rigidity. This contrasts with the research that is being done on PD, which has advanced rapidly, changing the face of the field. At the center of all this stands a simple messenger, dopamine. This article considers dopamine and its role in PD.
Dopamine in PD-like Disease
In the early 20th century, immediately after World War I, a plague swept the land for 10 years. People worldwide fell sick with encephalitis lethargica, first with fevers and headaches, followed by double vision, mental impairment, and lethargy. In many cases, this progressed to PD-like tremors, muscle rigidity and movement problems. As dramatized in the movie Awakenings, many patients had symptoms that approached catatonia and were institutionalized. Remarkably, treatment with levodopa (L-DOPA) “awakened” the catatonic or rigid patient. L-DOPA is a precursor for the neurotransmitter dopamine, which plays a central role in balancing the actions of other neurotransmitters in controlling muscle movements. The addition of L-DOPA produces a short term increase in dopamine and regain of muscle function; as the dopamine is cleared, muscle rigidity returns. In the case of the encephalitis plague, L-DOPA eventually lost its effectiveness following repeated administration, so patients could not be re-awakened. Fortunately, treatments have improved since then.
The story of Awakenings paints a vivid picture of a switch between normalcy and entombment in a living hell, an able mind trapped in a frozen body, with dopamine controlling the switch. Dopamine is a small molecule, produced by simple enzymatic modification of the amino acid tyrosine: L-tyrosine is converted to L-DOPA by tyrosine hydroxylase; DOPA carboxylase removes CO2 from L-DOPA to give dopamine. While it can be produced in a variety of sites in the body, the dopamine produced in neurons of the substantia nigra in the midbrain is important to motor control. These neurons extend to the basal ganglia, where dopamine is released to activate specific receptors. Five metabotropic dopamine GPCRs, numbered D1-5, have been identified. Two, D1 and D5, are excitatory and coupled to Gαs, which increases cAMP; D2-4 are inhibitory, coupled to Gαi and reduce cAMP. The phasic activation of D2, resulting in intermittent suppression of cAMP production by adenylyl cyclase, is thought to be important in PD-related motor control. Free dopamine in the synapse reenters neurons via a dopamine transporter to either be reused or degraded by catechol-O-methyl transferase and monoamine oxidases A and B.
The different subtypes of dopamine receptors are differentially distributed throughout the brain and body. Receptors D1, D2, and D4 are abundant in the limbic system, affecting emotion, memory, and behavior. The same receptors, and also D5, are found in the basal ganglia and contribute to voluntary motor control: fine motor movements may occur when not wanted, as in tremors, and attempted movements may be blocked or exaggerated. D1 and D5 on the hypothalamus and D2 in the pituitary inhibit the release of prolactin. Dopamine receptors are also found on smooth muscle cells of the cardiovascular system and contribute to contractility. So, in addition to motor control, dopamine contributes to diverse aspects related to learning and memory, pleasure and addiction, anxiety and pain, schizophrenia and psychosis. Dopamine is also metabolized by the enzyme dopamine β-hydroxylase to norepinephrine, which affects heart rate, glucose utilization, and blood pressure.
Parkinson’s Disease vs. Parkinsonism
As indicated above, PD is characterized by idiopathic neurodegeneration in the substantia nigra, associated with loss of dopaminergic neurons and loss of motor control. Additional symptoms are not necessary and are not implied in the diagnosis of PD. However, concurrent or developing symptoms may include: cognitive decline, dementia, daytime sleepiness, depression, anxiety, compulsive behavior, paranoia, hallucinations, loss of balance, problems with eating or speaking, urinary incontinence, or loss of smell. While motor dysfunction reflects faulty dopamine signaling in the basal ganglia, other symptoms may result from problems elsewhere in the brain. In fact, PD has been described as a progressive neurodegeneration that begins in the olfactory nucleus in the forebrain and moves to involve different parts of the midbrain, including the basal ganglia.1
PD has recently2 been divided into three distinct alternatives: 1) L-DOPA responsive parkinsonism, 2) a neuropathic state characterized by degeneration of the substantia nigra and formation of Lewy bodies (intraneuronal synuclein aggregates), and 3) L-DOPA responsive parkinsonism with Lewy bodies. Curiously, these categories are based on clinical and pathological criteria, ignoring causative factors. Parkinsonism, on the other hand, refers to the many situations where the common movement dysfunctions of PD (muscle rigidity, tremors) are secondary to another insult, such as infection. In reality, as researchers seek to understand the etiology of PD, they may come to agree that “PD is probably not a single nosological entity but instead it is more appropriate to think in terms of several different Parkinson’s diseases.”2 By so doing, it may be possible to treat the disease rather than the symptoms.
From a signaling perspective, anything that prevents dopamine activation of receptors in the basal ganglia would cause parkinsonism. In addition to loss of dopaminergic neurons, this could include impaired dopamine synthesis, dopamine trafficking or receptor function. Degeneration of neurons can result from a wide range of environmental, genetic, and physiological pathways. An excellent description of the potential causative factors of neurodegeneration and PD in people can be found at the website of Lifespan. There are several genetic and chemically-induced methods of neurodegeneration in mice and rats that, to some degree, model PD in humans. The mouse moguls at Jackson Laboratory have developed murine model repositories for PD as well as Alzheimer’s Disease (see jaxmice.jax.org/ findmice/repository.html). The PD repository includes several genetic mutants as well as strains that are susceptible or resistant to neurodegeneration induced chemically (using MPTP).
Stem Cells and Deep Brain Stimulation
The history of attempts to treat PD through surgery reads like a bad science fiction novel, except it’s true and the victims real. In many ways, the experience with stem cell therapy appears to be adding to the lore, while deep brain stimulation may be a breakthrough. The concept with stem cells is simple: replace lost dopamine-producing neurons by engrafting healthy neurons. The complications are many. Should the engrafted cells be fetal neurons, neural stem cells, embryonic stem cells, or adult stem cells? Should the cells be allowed to differentiate in the host brain or pre-differentiated in vitro? Should the cells be a monoculture of dopaminergic neurons or are supporting cells (astrocytes, glia) also needed? Would the addition of trophic factors, or trophic factor-supplying sources, help engraftment? With all of these complications, it may not be surprising that controlled studies of treating PD using stem cells in humans have not been encouraging.
While inserting electrodes into the brainstem may evoke Frankensteinian images, this is the approach used in deep brain stimulation. Electrodes are inserted through the skull and cortex until they reach the basal ganglia. Activation, using a pacemaker-like device, blocks signals within the globus pallidus and the subthalamic nucleus. This, in turn, helps control involuntary movements and other movement disorders. Deep brain stimulation has been effective in treating dyskinesias, but it is not without some down sides. First, there may be side effects, such as problems with apathy or decision making. Second, it only modulates symptoms but does not treat the disease or alter disease progression. Still, results have been promising and we can expect expanded use of this approach.
For further information, recent articles on deep brain stimulation,3 genetic PD4 and defining PD5 are suggested
References
1. Braak, H., Tredici, K.D., Rüb, U., et al. Neurobiol. Aging 24, 197-211 (2003).
2. Marras, C., Lang, A. Neurol. 70, 1996-2003 (2008).
3. Benarroch, E.E. Neurol. 70, 1991-1995 (2008).
4. Tobin, J.E., Latourelle, J.C., Lew, M.F., et al. Neurol. 71, 28-34 (2008).
5. Weiner, W.J. Arch. Neurol. 65, 705-708 (2008).
Dopamine/Parkinson’s-Related Products from Cayman
Products Notes
Tyrosine Hydroxylase (Phospho-Ser31) Polyclonal Antibody
Tyrosine Hydroxylase (Phospho-Ser19) Polyclonal Antibody
The rate-limiting enzyme in the synthesis of the catecholamines dopamine and norepinephrine.
Dopamine β-hydroxylase (C-Term; human) Polyclonal Antibody
Dopamine β-hydroxylase (N-Term; human) Polyclonal Antibody
Catalyzes the conversion of dopamine to norepinephrine and serves as a marker of noradrenergic cells.
Dopamine Transporter (Extracellular Loop 2) Polyclonal Antibody
Dopamine Transporter (C-Term) Polyclonal Antibody
Responsible for the reaccumulation of dopamine after it has been released
N-(α-Linolenoyl) Tyrosine
NALT enhances CNS dopamine content by facilitated transport of the tyrosine precursor across the blood-brain barrier.
Entacapone-d10
Increases the bioavailability of dopaminergic agents such as L-DOPA, by facilitating their passage across the blood-brain barrier.
2-PCPA (hydrochloride)
Irreversibly inhibits MAO A and MAO B with IC50 values of 2.3 and 0.95 µM and Ki values of 101.9 and 16 µM, respectively.
trans-Resveratrol
Inhibits human MOA-A and MOA-B.
2-PCPA (hydrochloride)
Inhibits human MOA-A and MOA-B with IC50 values of 25 and 61 µM, respectively.
PINK1 Polyclonal Antibody
PINK1 Blocking Peptide
Homozygous C-terminus mutation of PINK1 is associated with early onset of Parkinson’s
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