38 Neurodegenerative Diseases: Motor

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Neurodegenerative diseases cause neurons to lose either their function or structure over time, potentially leading to cell death in either the central or peripheral nervous system. These diseases can be devastating because there are no known ways to reverse the neurodegeneration. There are multiple diseases that are classified as neurodegenerative diseases and affect millions of people worldwide. We will focus on the two most prevalent neurodegenerative diseases: The motor disease Parkinson’s disease that affects the basal ganglia, and Alzheimer’s disease.

Parkinson’s Disease

Symptoms and Risk Factors

Parkinson’s disease is a neurodegenerative movement disorder that causes bradykinesia (slowness of movement), akinesia (difficulty initiating movement), a resting tremor, muscle rigidity, and changes to posture and locomotion. Although most symptoms are motor, there are mild cognitive and psychiatric changes, such as apathy, anhedonia, mood disturbances, or depression.

Figure 38.1. Parkinson’s disease. This drawing depicts the stooped posture and shuffling gait that are both symptoms of Parkinson’s disease.

Advanced age is the primary risk factor, as an estimated 2% of people over the age of 60 develop Parkinson’s disease. It is also shows a sex difference with men being diagnosed more than women. Other environmental factors contribute to risk, such as repeated traumatic brain injury (suspected in Muhammad Ali) or occupational exposure to heavy metals, insecticides, or other neurotoxins. A small percentage of cases are early onset (21 – 50 years old; Michael J. Fox was diagnosed at 30), and have a strong genetic component. The disease causes significant decreases in life expectancy and quality of life.

Basal Ganglia Dysfunction

A loss of dopaminergic neurons within the substantia nigra (a midbrain structure) contributes to basal ganglia circuitry disruption in Parkinson’s disease. This loss of substantia nigra cells can be visualized postmortem without the use of histology due to the natural black pigmentation of the substantia nigra cells.

The location of the substantia nigra in the midbrain and the loss of dopaminergic cells in Parkinson's disease.
Figure 38.2. Substantia nigra. The substantia nigra is a midbrain structure made up of dopaminergic neurons that project to the striatum. These dopaminergic cells are naturally pigmented black (substantia = substance, nigra = black). In Parkinson’s disease, these dopaminergic cells die, and a loss of the black pigmented cells can be observed in human cadavers.

When the substantia nigra cells die, they are no longer able to release dopamine at the striatum appropriately. When less dopamine is released into the striatum, the two populations of striatal neurons are affected differently dependent on the type of dopamine receptor that they express. Recall the basal ganglia circuitry from the previous chapter.

Direct Pathway Dysfunction

Within the direct pathway, striatal cells (within the caudate) express excitatory D1 receptors that project  directly to the globus pallidus internal segment. In the direct pathway, typically, dopamine binds to D1 receptors on striatal neurons, increasing caudate activity. These striatal neurons release GABA onto the globus pallidus internal segment (GPi) neurons, causing the GPi neurons to be less active. When the Gpi neurons are less active, they release less GABA onto the thalamic neurons, increasing thalamic neuron activity and the excitatory projections to the motor cortex, thus increasing movement.

In Parkinson’s disease, there is decreased release of dopamine onto the striatal caudate neurons that express D1 receptors, making them less active. Now that the striatal neurons are not as active, they release less GABA onto GPi neurons, disinhibiting them. The GPi is now more active, releasing more GABA onto thalamic neurons. In response, the thalamic neurons are less active and send less excitatory messages to the cortex, thus causing a decrease in movement overall.

Comparison of how D1 receptor activation between healthy individuals and those with Parkinson's disease.
Figure 38.3. Changes in D1 Receptor activity in Parkinson’s disease. A. In healthy individuals, the substantia nigra releases dopamine onto striatal cells in the caudate. The caudate expresses D1 receptors that are excitatory. When dopamine binds to D1 receptor it causes EPSPs in the caudate neurons, and an increase in activity of the caudate neuron. B. The striatal neurons are GABAergic, so when activity is increased in healthy individuals, they release more GABA onto GPi neurons. GABA binds to receptors on the GPi neurons, causing an influx of Cl- ions and membrane hyperpolarization, leading to less activity. C. In individuals with Parkinson’s disease, the dopaminergic substantia nigra cells die, and as a result do not release dopamine onto caudate neurons. This causes a decrease in activity of the caudate neurons. D. Decreased activity of the caudate neurons leads to decreased release of GABA onto the GPi neurons. As a result, the GPi neurons have increased activity. ‘Changes in D1 Receptors activity in Parkinson’s disease’ by Valerie Hedges is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Model of basal ganglia circuitry.
Figure 38.4. Model of Basal Ganglia Circuitry in Parkinson’s disease- Direct Pathway.  This model shows the dopaminergic, glutamatergic, and GABAergic connections within the basal ganglia circuitry. Tonically active connections are indicated. The direct pathway is highlighted with orange. Larger arrows indicate increased activity, and smaller arrow indicated decreased activity. The cortex provides glutamatergic input to the striatum, which also receives dopaminergic projections from the substantia nigra. In Parkinson’s disease, the dopaminergic neurons die and there is a loss of dopaminergic input into the striatum. As a result, the decreased D1 receptor activation in the caudate causes the caudate cells to be less active, releasing less GABA onto the globus pallidus internal segment. The globus pallidus internal segment is disinhibited, and thus increases its firing rate, releasing more GABA onto the thalamus. The decreased D2 receptor activation in the putamen causes the putamen cells to be more active, releasing more GABA onto the globus pallidus external segment. The globus pallidus releases less GABA onto the subthalamic nucleus. The subthalamic nucleus is disinhibited, and increases its release of glutamate onto the GPi. This causes the GPi to increase its firing rate, releasing more GABA onto the thalamus. Together, the decreased activity of the thalamus decreases activity of the motor cortex and thus decreases movement. ‘Model of Basal ganglia circuitry in Parkinson’s disease- direct pathway’ by Valerie Hedges is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Indirect Pathway Dysfunction

In the indirect pathway, dopamine typically binds to inhibitory D2 receptors on striatal (putamen) neurons, inhibiting striatal neuron activity. These striatal neurons then release less GABA onto the globus pallidus external segment neurons (GPe), causing the GPe neurons to be more active. When the GPe neurons are more active, they release more GABA onto the subthalamic nucleus neurons, decreasing subthalamic neuron activity and the excitatory projections to the GPi.  Decreasing activation of the GPi causes the GPi to release less GABA onto the thalamus, which then causes more activation of the motor cortex,  thus increasing movement.

In Parkinson’s disease, there is decreased release of dopamine onto the striatal neurons that express D2 receptors, making them more active. Now that the striatal neurons are more active, they release more GABA onto GPe neurons. This inhibits the GPe neurons, causing them to release less GABA onto subthalamic nucleus neurons, disinhibiting the subthalamic nucleus. Increasing the excitatory inputs from the subthalamic nucleus onto the GPi will cause the GPi to release more GABA onto the thalamus. In response, the thalamic neurons are less active and send less excitatory messages to the cortex, thus causing a decrease in movement overall.

Figure 38.5. Parkinson’s disease effect on indirect pathway. Changes in D2 Receptor activity in Parkinson’s disease. A. In healthy individuals, the substantia nigra releases dopamine onto striatal cells in the putamen. The putamen expresses D2 receptors that are inhibitory. When dopamine binds to D2 receptor it causes IPSPs in the putamen neurons, and an decrease in activity of the putamen neuron. B. The striatal neurons are GABAergic, so when activity is decreased in healthy individuals, they release less GABA onto GPe neurons. Decreased activity of the caudate neurons leads to decreased release of GABA onto the GPi neurons. As a result, the GPe neurons have increased activity. C. In individuals with Parkinson’s disease, the dopaminergic substantia nigra cells die, and as a result do not release dopamine onto putamen neurons. This causes an increase in activity of the putamen neurons. D. Increased activity of the putamen neurons leads to increased release of GABA onto the GPe neurons. As a result, the GPe neurons have decreased activity. ‘Changes in D2 Receptors activity in Parkinson’s disease’ by Valerie Hedges is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Basal ganglia circuitry model.
Figure 38.6. Model of Basal Ganglia Circuitry in Parkinson’s disease- Indirect Pathway.  This model shows the dopaminergic, glutamatergic, and GABAergic connections within the basal ganglia circuitry. Tonically active connections are indicated. The indirect pathway is highlighted with orange. Larger arrows indicate increased activity, and smaller arrow indicated decreased activity. The cortex provides glutamatergic input to the striatum, which also receives dopaminergic projections from the substantia nigra. In Parkinson’s disease, the dopaminergic neurons die and there is a loss of dopaminergic input into the striatum. As a result, the decreased D1 receptor activation in the caudate causes the caudate cells to be less active, releasing less GABA onto the globus pallidus internal segment. The globus pallidus internal segment is disinhibited, and thus increases its firing rate, releasing more GABA onto the thalamus. The decreased D2 receptor activation in the putamen causes the putamen cells to be more active, releasing more GABA onto the globus pallidus external segment. The globus pallidus releases less GABA onto the subthalamic nucleus. The subthalamic nucleus is disinhibited, and increases its release of glutamate onto the GPi. This causes the GPi to increase its firing rate, releasing more GABA onto the thalamus. Together, the decreased activity of the thalamus decreases activity of the motor cortex and thus decreases movement. ‘Model of Basal ganglia circuitry in Parkinson’s disease- indirect pathway’ by Valerie Hedges is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Diagnosis and Treatment

Parkinson’s disease is considered idiopathic because there is not a single known cause. Unfortunately, there are not measurable biomarkers (blood tests, brain scans) to diagnose Parkinson’s disease. Rather, diagnosis of individuals is typically done by a neurologist and a detailed exam. This can be further confirmed by giving medications that are used to treat Parkinson’s disease and determining if symptoms decrease.

A diagnosis of Parkinson’s disease is confirmed post-mortem through:

  1. The loss of dopaminergic substantia nigra cells.
  2. Presence of Lewy bodies.

Lewy bodies are intracellular alpha-nuclein protein aggregates that are believed to potentially displace healthy neurons and lead to the neurodegeneration observed in the disease.

Microscope image of a Lewy body.
Figure 38.7. Lewy bodies. This microscope image is showing a Lewy body (denoted by the black triangle) in the substantia nigra of an individual with Parkinson’s disease.

Dopamine cannot be administered as a treatment to those with Parkinson’s disease to replace the loss of dopamine from the substantia nigra due to the inability of dopamine to cross the blood-brain-barrier. Instead, the major drug treatment for the motor symptoms of Parkinson’s disease has been administration of the drug levodopa (L-DOPA). L-DOPA is an intermediate in the synthesis of dopamine. Typically, it is converted into dopamine through the activity of DOPA decarboxylase. It is typically co-administered with other drugs to help prolong its effects. Unfortunately, there are many side effects of L-DOPA including nausea, joint stiffness, dyskinesias (involuntary movements and tics), and psychosis.

Dopamine synthesis pathway.
Figure 38.8. Dopamine synthesis pathway. Tyrosine is converted into L-DOPA through tyrosine hydroxylase. L-DOPA is then converted into dopamine by the enzyme DOPA decarboxylase. ‘Dopamine Synthesis’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License.

In a medical intervention called deep brain stimulation (DBS), a surgeon implants permanently indwelling electrodes directly into brain tissue. These electrodes are controlled by an external battery pack that delivers preprogrammed stimulation protocols. DBS in the STN is used to alleviate the symptoms of Parkinson’s disease.

Deep brain stimulation device.
Figure 38.9. Deep brain stimulation. A deep brain stimulator device must be implanted surgically. Electrodes are positioned in specific brain areas for the delivery of electrical impulses. The impulses come from an external battery pack that is typically implanted beneath the skin on the chest. Deep brain stimulation can be used to treat disorders such as Parkinson’s disease, obsessive compulsive disorder, and depression.

Key Takeaways

  • Parkinson’s disease is a neurodegenerative disease that causes dopaminergic substantia nigra cells to die, causing dysfunction in the basal ganglia circuitry.
  • L-DOPA and deep brain stimulation are treatments for Parkinson’s disease.

Attributions

This chapter is adapted from “Neurodegenerative Diseases: Motor” in Introduction to Neuroscience by Valerie Hedges which is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

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Introduction to Neurobiology Copyright © 2024 by Avinash Singh is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, except where otherwise noted.

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