Parkinson’s disease is a progressive neurodegenerative disorder that affects movement and coordination. The hallmark symptoms of Parkinson’s disease are tremors, rigidity, slowness of movement (bradykinesia), and difficulty with walking and balance. These motor symptoms are caused by the progressive loss of dopamine-producing neurons in a part of the brain called the substantia nigra. Dopamine is an important neurotransmitter that helps control movement and coordination. As dopamine levels in the brain steadily decline due to the loss of these neurons, the motor symptoms of Parkinson’s emerge and worsen over time. Understanding what exactly is lacking in the brain in Parkinson’s disease is key to developing better treatments and hopefully one day a cure.
What causes the loss of dopamine neurons in Parkinson’s?
The exact causes of the progressive death of dopamine neurons in the substantia nigra are not fully understood. However, research has uncovered several factors that likely contribute:
Lewy bodies
Abnormal clusters of proteins called Lewy bodies accumulate in dopamine neurons, causing them to malfunction and eventually die. The main component of Lewy bodies is alpha-synuclein protein. The clumping of this protein disrupts normal cell functioning.
Mitochondrial dysfunction
Mitochondria act as the powerhouses of cells, generating energy. In Parkinson’s, mitochondria in dopamine neurons become dysfunctional, impairing energy production and increasing oxidative stress. This metabolic stress can eventually lead to cell death.
Neuroinflammation
Chronic inflammation in the brain, likely triggered by factors like Lewy bodies, can activate the immune system and cause it to attack and kill dopamine neurons over time.
Genetics
While most cases of Parkinson’s are sporadic, about 10-15% of cases are caused by inherited genetic mutations. These faulty genes can increase susceptibility to dopamine neuron loss via mechanisms like mitochondrial dysfunction or alpha-synuclein buildup.
What happens in the brain as dopamine neurons die off?
As more and more dopamine neurons in the substantia nigra deteriorate and die off, there is a progressive depletion of dopamine supply to other areas of the brain. This dopamine deficiency causes dysregulation in brain regions that rely on dopamine signaling to function properly, leading to the motor symptoms seen in Parkinson’s:
The basal ganglia
The basal ganglia are a group of nuclei involved in control of voluntary movement. Dopamine helps regulate signaling in two main basal ganglia pathways – the direct and indirect pathways. When dopamine is lacking, activity in these pathways becomes imbalanced. This impairs their ability to smoothly regulate body movements.
The motor cortex
The motor cortex is the main brain region involved in generating and executing voluntary movements. Without enough dopamine, abnormal signaling patterns emerge between the basal ganglia and motor cortex. This prevents the motor cortex from properly activating muscles to initiate movements.
The cerebellum
The cerebellum coordinates balance and fine-tuning of movements. Declining dopamine disrupts the cerebellum’s precision control over motor coordination. This can cause the tremors, balance issues, and walking difficulties seen in Parkinson’s.
What brain imaging reveals about dopamine loss in Parkinson’s
Advanced brain imaging techniques have allowed researchers to visualize the progressive loss of dopamine function in Parkinson’s:
PET scans
PET (positron emission tomography) scans use radioactive tracers to image dopamine activity in the brain. PET scans of Parkinson’s patients show reduced dopamine synthesis and transporter function in the striatum, part of the basal ganglia. This reflects the loss of dopamine neurons projecting from the substantia nigra.
fMRI scans
Functional MRI scans measure changes in blood flow and oxygen levels in the brain during tasks. fMRI reveals abnormal activation patterns in the basal ganglia and motor cortex of Parkinson’s patients as they attempt motor tasks. This shows impaired signaling in these dopamine-reliant regions.
SPECT scans
SPECT (single photon emission computed tomography) uses injected radioactive tracers to measure blood flow and dopamine transporters. SPECT scans can identify reduced dopamine activity specifically within the substantia nigra region in Parkinson’s.
| Imaging Technique | What is Measured | Key Findings in Parkinson’s Brains |
|---|---|---|
| PET | Dopamine synthesis and transport | Reduced dopamine activity in striatum |
| fMRI | Blood flow and oxygenation | Abnormal activation in basal ganglia and motor cortex |
| SPECT | Blood flow and dopamine transporters | Decreased dopamine in substantia nigra |
How does dopamine loss impact neurological symptoms?
The worsening dopamine deficit as Parkinson’s progresses is directly linked to the emergence and increasing severity of motor symptoms:
Tremors
Tremors occur due to the impaired ability of the basal ganglia and cerebellum to smoothly regulate muscle contractions without enough dopamine. Tremors often first appear unilaterally in the hands at rest.
Rigidity
Rigidity and stiffness of the limbs results from over-activation of motor neurons controlling muscle tone. Declining dopamine leads to imbalance between direct/indirect basal ganglia pathways that regulate muscle tone.
Bradykinesia
Slowness of movement is caused by under-activation of the motor cortex due to abnormal signaling from dopamine-depleted basal ganglia. This reduces speed and amplitude of muscle contractions.
Balance and coordination issues
Impaired signaling between the basal ganglia, motor cortex, and cerebellum makes coordination and balancing difficult. This affects walking, posture, and fine motor skills.
Freezing of gait
Episodes where patients are unable to initiate movement or “freeze” in place are linked to severe dopamine loss. The exact mechanisms behind freezing are unclear.
Non-motor symptoms also result from dopamine deficits
In addition to motor impairment, the lack of dopamine causes many non-motor symptoms due to dopamine’s role in mood, motivation, cognition, sleep, and autonomic function:
Depression and anxiety
Depleted dopamine levels can lead to depression and anxiety in up to 50% of Parkinson’s patients. Dopamine regulates mood and motivation.
Cognitive impairment
Loss of dopamine neurons contributes to mild cognitive impairment in the early stages of Parkinson’s. As dopamine signaling worsens, dementia can occur in the later stages.
Sleep disorders
Disruptions to dopamine signaling pathways involved in the sleep-wake cycle can cause insomnia, daytime sleepiness, and REM sleep behavior disorder.
Autonomic dysfunction
Constipation, urinary issues, orthostatic hypotension, and sexual dysfunction stem from dopamine’s role in regulating the autonomic nervous system.
Current treatments aim to replace lost dopamine
Since the motor and non-motor symptoms of Parkinson’s arise from low dopamine levels, current treatments focus on restoring dopamine function in the brain:
Levodopa
Levodopa is a dopamine precursor that crosses the blood-brain barrier and converts to dopamine. It is the most effective medication for improving motor symptoms by replenishing dopamine.
Dopamine agonists
These drugs mimic dopamine by binding to dopamine receptors in the brain to stimulate dopamine-like activity. Examples are pramipexole, ropinirole, and rotigotine.
MAO-B inhibitors
These prevent the breakdown of dopamine by inhibiting the enzyme monoamine oxidase B. This leaves more dopamine available in the brain. Examples are selegiline and rasagiline.
Deep brain stimulation
This neurosurgical treatment uses implanted electrodes to deliver electrical pulses that modulate abnormal brain signaling patterns caused by low dopamine.
However, current treatments have limitations. Levodopa can cause side effects like dyskinesias with long-term use. And no therapies halt the progressive loss of dopamine neurons – they only help manage symptoms.
Research into disease-modifying therapies
Exciting research is underway to try to develop disease-modifying therapies that could slow, stop, or reverse the death of dopamine neurons. Possible strategies being investigated include:
Neuroprotective agents
Compounds that block oxidative stress, inflammation, and other processes toxic to neurons may be able to protect dopamine neurons from further damage.
GDNF
Glial cell line-derived neurotrophic factor (GDNF) is a protein that nourishes dopamine neurons and promotes their growth and survival. GDNF delivery to the brain may preserve dopamine neurons.
Gene therapies
Introducing healthy genes into dopamine neurons via viral vectors could potentially prevent cell death by overriding damaged genes linked to Parkinson’s.
Stem cell therapies
Transplanting stem cell-derived dopamine neurons into the brain may replenish lost dopamine production capacity if the neurons can successfully integrate.
Immunotherapies
Therapies that prompt the immune system to clear out toxic alpha-synuclein proteins or stop attacking dopamine neurons may halt Parkinson’s progression.
Conclusion
In Parkinson’s disease, the hallmark motor and non-motor symptoms emerge as dopamine neurons in the substantia nigra deteriorate and die off. This leads to steadily declining dopamine levels and dysregulation of brain regions relying on dopamine signaling. While current treatments temporarily alleviate symptoms, future disease-modifying therapies that protect remaining dopamine neurons from death could be the key to stopping Parkinson’s in its tracks. Understanding the neuroscience behind what goes wrong in the Parkinson’s brain is crucial for developing more effective treatments.