Parkinson’s Disease: Causes, Symptoms, Genetic Factors, Diagnosis, Risk Factors and Treatment

Table of Contents

• Introduction to Parkinson's Disease (PD)
• Causes of Parkinson’s disease
• Genetic Causes of Parkinson’s Disease
• Symptoms of Parkinson’s disease
• Complications related to Parkinson’s disease
• Risk Factors of Parkinson’s Disease
• Diagnosis of Parkinson’s disease
• Treatments of Parkinson’s disease
• References

Introduction to Parkinson's Disease (PD)

• Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which neurons in specific regions of the brain become impaired, lose their normal function, and eventually die.
• The loss and dysfunction of these neurons disrupt normal motor control, leading to characteristic movement-related symptoms.
• Common symptoms of Parkinson’s disease include:
• Tremor, particularly when the body is at rest
• Muscle stiffness (rigidity)
• Difficulty with movement (bradykinesia)
• Impaired balance and coordination
• As the disease progresses, individuals may experience difficulties with walking, speaking, and performing everyday tasks.
• Parkinson’s disease is a major neurological disorder affecting millions of people worldwide, with more than 10 million people estimated to be living with the disease globally.
• The prevalence of Parkinson’s disease increases with age, affecting approximately 3% of people by the age of 65 and up to 5% of people over 85 years of age.

Causes of Parkinson’s Disease

• The exact cause of Parkinson’s disease (PD) has not been fully established. Current evidence suggests that PD develops through a complex interaction between genetic susceptibility and environmental factors.
• Most Parkinson’s disease cases are sporadic, meaning no specific cause or inherited mutation can be identified.
• Approximately 10% of Parkinson’s disease cases are associated with inherited disease-causing genetic mutations, while the majority have no clearly identifiable genetic cause.

Progression of Parkinson’s Disease in the Substantia Nigra

• A major feature of Parkinson’s disease is the progressive degeneration and loss of dopaminergic neurons in a brain region called the substantia nigra, located near the base of the brain.
• These neurons normally produce dopamine, a neurotransmitter that plays an essential role in transmitting signals involved in the control and coordination of movement.
• As dopaminergic neurons are lost, dopamine levels decrease, disrupting the neural circuits responsible for normal motor control.
• The resulting dopamine deficiency contributes to characteristic motor symptoms such as tremor, rigidity, slowness of movement, and impaired coordination.

Dopamine and Norepinephrine Pathways Affected by Parkinson’s Disease

• Parkinson’s disease also involves degeneration of nerve endings that produce norepinephrine (noradrenaline), another important neurotransmitter.
• Norepinephrine helps regulate several automatic (autonomic) functions of the body, including blood pressure and heart rate.
• Reduced norepinephrine signaling may therefore contribute to several non-motor symptoms associated with Parkinson’s disease.

Lewy Bodies and Alpha-Synuclein

• Parkinson’s disease is also characterized by the accumulation of abnormal clumps of the protein alpha-synuclein within the cytoplasm of surviving neurons.
• These abnormal protein aggregates are known as Lewy bodies.
• Abnormal accumulation and aggregation of alpha-synuclein are strongly associated with the neurodegenerative processes observed in Parkinson’s disease.

Genetic Causes of Parkinson’s Disease

Several genes have been identified as being associated with an increased risk of Parkinson’s disease or inherited forms of the disorder:

SNCA Gene

• The SNCA (alpha-synuclein) gene encodes the alpha-synuclein (α-synuclein) protein, a neuronal protein that is abundant in the brain and involved in synaptic vesicle regulation.
• Certain SNCA mutations or gene duplications can increase the production or alter the behavior of alpha-synuclein.
• Abnormal alpha-synuclein can accumulate and form protein aggregates, contributing to neurodegenerative processes associated with Parkinson’s disease.

LRRK2 Gene

• The LRRK2 (leucine-rich repeat kinase 2) gene encodes dardarin, a large protein expressed in the brain and other tissues.
• LRRK2 has both kinase and GTPase-related activities and participates in several cellular processes.
• Certain LRRK2 variants are associated with Parkinson’s disease and may influence alpha-synuclein accumulation and other cellular pathways involved in neurodegeneration.

PINK1 Gene

• PINK1 (PTEN-induced kinase 1) is a mitochondrial protein involved in the detection and removal of damaged mitochondria.
• When mitochondria become damaged, PINK1 accumulates on their membranes and helps activate ubiquitin-dependent pathways, promoting their removal through a process known as mitophagy.
• Mutations in the PINK1 gene (PARK6) can impair mitochondrial quality control.
• The accumulation of dysfunctional mitochondria can increase cellular stress and is associated with early-onset Parkinson’s disease.

PRKN (Parkin) Gene

• The PRKN (Parkin) gene encodes the parkin protein, an E3 ubiquitin ligase involved in cellular protein and mitochondrial quality control.
• Parkin helps label damaged cellular components with ubiquitin, marking them for degradation or removal.
• Mutations in PRKN can impair these quality-control mechanisms and are associated with autosomal recessive Parkinson’s disease, particularly early-onset forms.

DJ-1 (PARK7) Gene

• The PARK7 gene encodes DJ-1, a protein involved in protecting cells against oxidative stress and maintaining redox balance.
• DJ-1 also contributes to mitochondrial function and cellular protection.
• Mutations in PARK7 can impair these protective mechanisms and are associated with certain forms of early-onset Parkinson’s disease.

GBA Gene

• The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which contributes to the maintenance of glycosphingolipid homeostasis and normal lysosomal function.
• Certain GBA mutations cause Gaucher disease, a lysosomal storage disorder, while GBA variants are also an important genetic risk factor for Parkinson’s disease.
• Approximately 10–15% of people with Parkinson’s disease may carry a GBA variant, although the exact frequency varies among populations and study groups.
• GBA-associated Parkinson’s disease can be linked with more severe and faster-progressing motor and non-motor symptoms in some individuals.

Parkinson’s Disease as a Hypokinetic Disorder

• Parkinson’s disease is classified as a hypokinetic movement disorder because it is characterized by reduced or slowed voluntary movement.
• The progressive loss of dopaminergic neurons and resulting disruption of dopamine signaling are central to the development of its characteristic motor symptoms.

Symptoms of Parkinson’s disease

• The symptoms of Parkinson’s disease (PD) vary considerably from person to person, and the rate of disease progression also differs among individuals.
• Symptoms often begin on one side of the body and may gradually progress to involve both sides.
• The four major motor symptoms of Parkinson’s disease are tremor, rigidity, bradykinesia, and postural instability.

1. Tremor (Shaking)

• Tremor is a rhythmic, involuntary shaking that commonly begins in the hands, but may also affect the feet or jaw.
• Parkinsonian tremor is typically most noticeable when the affected body part is at rest and may become more pronounced during stress or emotional tension.
• The tremor generally disappears during sleep and may decrease during purposeful or intentional movement.

2. Rigidity (Muscle Stiffness)

• Rigidity causes the muscles to become tight, tense, and stiff, which may result in muscle discomfort or aching.
• When an affected limb is moved passively, the movement may feel slow, stiff, or jerky.
• A characteristic form called cogwheel rigidity produces a ratchety, stop-and-go sensation during movement.

3. Bradykinesia (Slowness of Movement)

• Bradykinesia refers to a progressive slowness of voluntary and automatic movements.
• It can make everyday activities that are normally performed quickly and easily more difficult and time-consuming.
• Individuals may also develop reduced facial expressions, resulting in a less expressive appearance.

4. Postural Instability

• Postural instability refers to impaired balance and reduced ability to maintain a stable posture.
• As Parkinson’s disease progresses, changes in posture, balance, and coordination can increase the risk of falls.

Parkinsonian Gait

• People with Parkinson’s disease may develop a characteristic walking pattern known as a Parkinsonian gait.
• Typical features include:
• Leaning forward while walking
• Taking small, rapid steps
• Reduced or absent arm swing on one or both sides
• Hesitation when initiating movement
• Sudden stopping or freezing of gait, in which the person temporarily feels unable to move their feet

Juvenile Parkinsonism

• In rare cases, Parkinsonian symptoms can develop at a much younger age, sometimes around or before 20 years of age.
• Parkinsonism occurring at such an early age is referred to as juvenile Parkinsonism.

Complications related to Parkinson’s disease

• Mental health problems: Depression and anxiety are common in people with Parkinson’s disease and may occur even during the early stages of the condition.
• Difficulty in speech: Speech may become soft, slow, or monotonous. Some individuals may hesitate before speaking, while others may speak rapidly or with slurred speech.
• Skin problems: Increased oil production, particularly around the nose and forehead, can cause oily skin. Changes in sweating may also contribute to dry or irritated skin.
• Sleep problems: Sleep disturbances are common and may be associated with changes in circadian rhythm and other effects of Parkinson’s disease. Individuals may experience restless sleep, nightmares, vivid or emotionally intense dreams, excessive daytime sleepiness, and sudden episodes of falling asleep during the day. REM sleep behavior disorder (RBD) may cause individuals to physically act out their dreams, potentially resulting in injury to themselves or their bed partners.
• Dementia and cognitive problems: Some individuals develop memory problems, impaired thinking, and slowed cognitive processing. These difficulties may become more pronounced as the disease progresses.
• Difficulty swallowing and chewing: In advanced Parkinson’s disease, impaired control of the muscles involved in chewing and swallowing can make eating difficult. Food and saliva may accumulate in the mouth or throat, increasing the risk of choking and aspiration.
• Pain, muscle cramps, and dystonia: Muscle rigidity and reduced movement can cause painful muscle cramps, particularly in the legs and toes. Some individuals may also develop dystonia, characterized by sustained involuntary muscle contractions that can produce abnormal or twisted postures.
• Fatigue: Persistent or severe fatigue is common and may result from the increased effort required to perform movements and everyday activities.

Risk Factors of Parkinson’s Disease

• Age: The risk of developing Parkinson’s disease increases with advancing age, with the condition being most commonly diagnosed around the mid-60s. However, Parkinson’s can also occur at a younger age, including before 50 years, in cases of young-onset Parkinsonism.
• Heredity: A family history of Parkinson’s disease can increase an individual’s risk. Although most cases are sporadic, people who have one or more close relatives with Parkinson’s disease may have a higher likelihood of developing the condition, particularly when specific genetic variants are involved.
• Biological Sex: Parkinson’s disease is generally more common in males than females, with studies suggesting that men have approximately twice the risk of developing the disease. However, women with Parkinson’s may experience faster disease progression and higher mortality in some populations.
• Environmental Exposure: Long-term exposure to certain environmental toxins and occupational hazards may increase the risk of Parkinson’s disease. Reported risk factors include exposure to pesticides, particularly in agricultural or rural settings, and certain toxic substances. MPTP, a neurotoxic compound associated with illicit drug exposure, can cause Parkinsonian symptoms, while manganese exposure, such as in some metal-welding occupations, has also been associated with Parkinsonism.
• Chronic Stress and Occupational Factors: Prolonged psychological stress and occupations involving high job demands have been investigated as potential risk factors, although the relationship between chronic stress and Parkinson’s disease remains complex and is not considered a definitive cause.

Diagnosis of Parkinson’s disease

• There is currently no single definitive test that can diagnose Parkinson’s disease (PD), particularly in its early stages.
• Blood tests and routine laboratory tests cannot directly diagnose most non-genetic cases of Parkinson’s disease.
• Diagnosis is primarily based on the individual’s medical history, pattern and progression of symptoms, and neurological examination.
• During the neurological examination, healthcare professionals assess features such as movement, muscle rigidity, tremor, balance, coordination, and reflexes.
• In the early stages, Parkinson’s disease can be difficult to distinguish from other Parkinsonian disorders with similar symptoms.
• Conditions such as dementia with Lewy bodies and multiple system atrophy may initially resemble Parkinson’s disease, which can result in diagnostic errors.
• An inaccurate diagnosis may lead to inappropriate or less effective medical management.
• Therefore, improving the early and accurate diagnosis of Parkinson’s disease remains an important area of clinical research.

Treatments of Parkinson’s disease

• Although there is currently no cure for Parkinson’s disease (PD), its symptoms can be managed through a combination of medications, surgical procedures, and therapeutic lifestyle approaches.
• Treatment is individualized according to the person’s symptoms, disease stage, response to treatment, and overall health.

Medication

Medications used to manage Parkinson’s disease can be broadly grouped into three categories according to how they help relieve symptoms:

• Increasing dopamine levels or activity in the brain
• Modulating other neurotransmitters involved in Parkinson’s symptoms
• Managing non-motor symptoms associated with the disease
• Major medications used in Parkinson’s disease include:

Levodopa

• Levodopa is the most effective and commonly used medication for controlling the motor symptoms of Parkinson’s disease.
• It is a precursor of dopamine and can cross the blood-brain barrier, where it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC).
• By replenishing dopamine in the brain, levodopa helps improve symptoms such as bradykinesia and rigidity.
• Levodopa is commonly administered with carbidopa as a combination known as levodopa-carbidopa.
• Carbidopa inhibits the conversion of levodopa into dopamine outside the brain, allowing more levodopa to reach the brain and reducing peripheral adverse effects such as nausea, vomiting, low blood pressure, and restlessness.

Dopamine agonists

• Dopamine agonists are medications that mimic the effects of dopamine by binding to and activating dopamine receptors in the brain.
• They may be used alone or in combination with levodopa, particularly during earlier stages of Parkinson’s disease.

Enzyme inhibitors

• Certain enzymes break down dopamine and thereby reduce its availability in the brain.
• Monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors inhibit dopamine metabolism, helping to prolong or enhance dopamine activity in the brain.
• These medications are often used as adjuncts to levodopa therapy.

Anticholinergic drugs

• Anticholinergic medications, such as benztropine, trihexyphenidyl, and ethopropazine, reduce the activity of the neurotransmitter acetylcholine.
• They may help reduce tremor and muscle rigidity, although their use is generally limited because of potential adverse effects, particularly in older adults.

Amantadine

• Amantadine was originally developed as an antiviral medication but also has effects on dopaminergic signaling.
• It can help manage certain Parkinson’s symptoms and is particularly useful for reducing levodopa-induced involuntary movements (dyskinesia) in appropriate patients.

Surgery

Surgical treatment may be considered for people with Parkinson’s disease whose symptoms are not adequately controlled with medication or who experience significant medication-related complications.
Two surgical approaches include:

Lesion surgery

• Lesion surgery involves intentionally creating a small, targeted lesion in a specific brain region involved in abnormal movement.
• One example is pallidotomy, in which part of the globus pallidus is selectively lesioned to reduce symptoms such as rigidity, tremor, and bradykinesia.
• Because lesioning causes permanent changes to brain tissue, these procedures are used less frequently than reversible neuromodulation approaches such as deep brain stimulation.

Deep Brain Stimulation

• Deep brain stimulation (DBS) is an established surgical treatment for selected people with Parkinson’s disease, particularly those with disabling motor symptoms or significant motor fluctuations despite medication.
• In subthalamic nucleus deep brain stimulation (STN-DBS), electrodes are implanted into targeted areas of the brain involved in movement control.
• The electrodes are connected by wires under the skin to a small pulse generator implanted in the chest.
• The generator delivers controlled electrical stimulation to the targeted brain region, helping regulate abnormal neural activity.
• DBS can significantly reduce symptoms such as tremor, rigidity, and slowness of movement in appropriately selected patients.
• Unlike lesion surgery, DBS does not intentionally destroy the targeted brain tissue and its stimulation settings can be adjusted after implantation.

Other therapies

• Physical therapy can help improve strength, mobility, balance, flexibility, and coordination and may help maintain independence in daily activities.
• Occupational therapy can assist individuals in adapting everyday activities and improving their ability to perform routine tasks safely.
• Speech and language therapy can help address problems involving speech, voice, communication, and swallowing.
• Regular exercise and physical activity are generally encouraged to support mobility, strength, flexibility, balance, and overall physical function.
• Massage therapy and relaxation or meditation practices may help reduce muscle tension, stress, and improve overall well-being, although they do not treat the underlying neurodegeneration.
• A balanced and nutritious diet supports general health and well-being. Adequate fiber and fluid intake can also help manage constipation, which is common in Parkinson’s disease.
• Dietary timing and composition can affect levodopa absorption. In particular, protein-containing meals can compete with levodopa for absorption and transport, so some individuals may benefit from individualized dietary guidance from a healthcare professional rather than simply increasing fiber or fluids to alter levodopa absorption.

Disclaimer: The information presented on this website is intended for academic, educational, study, and general informational purposes only. It should not be used as a substitute for professional medical advice, diagnosis, or treatment. If you have symptoms, concerns, or questions about Parkinson’s disease or its treatment, consult a qualified physician or other appropriate healthcare professional.

References

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• Parkinson’s Foundation. (n.d.). Statistics. Retrieved May 3, 2025, from https://www.parkinson.org/understanding-parkinsons/statistics