Parkinson Disease

Background

Parkinson Disease (PD) is a chronic progressive neurodegenerative disorder. It was first described by James Parkinson 1817. It is a member of the group of motor system disorders, which occur because of the loss of dopamine-producing brain cells. As explained by Southwestern Medical Center, PD is a result of a cascade of events in the nervous system:

When dopamine-producing neurons die, loss of dopamine release in the striatum causes the acetylcholine producers there to overstimulate their target neurons, thereby triggering a chain reaction of abnormal signaling leading to impaired mobility

PD affects around 1-1.5 million people in the US. Symptoms generally appear when the patient is 50 years or older. However, there is an early-onset PD which can occur in people 40 and younger.

Symptoms

Primary symptoms

• Bradykinesia - slowness in voluntary movement due to delayed transmission signals between the brain and muscles
• Tremors - most commonly occur in the hands, fingers, forearms, feet, mouth, and chin, when these muscles are at rest
• Rigidity - painful stiffening of muscles that worsens during movement
• Poor balance - occurs due to lessening of reflexes that maintain posture
• Parkinson's gait - walk distinctive to PD that includes leaning unnaturally forward or backward, stooping, head and shoulders drooped, and minimal arm swing. Commencing walking may be difficult and it is common to halt in the middle of a stride.

Secondary symptoms

Patients may experience some, but generally not all, of the following symptoms. Severity varies between individuals:

Constipation, difficulty chewing and swallowing, excessive salivation or sweating, bowel/bladder control difficulties, loss of intellectual capacity, psychosocial problems, dry skin, and soft voice

This site demonstrates the neural pathways that lead to PD symptoms.

Genes

Until recently, PD was thought to be caused by environmental, not genetic factors. However, studies within the past decade have found a number of genes associated with the disease.

Polymeropoulos, et al. (1996) located a gene marker for PD in the 4q21-q23 region.

Further studies have specified particular genes involved in PD. This NLM site lists some of the genes involved and inheritance patterns:

• Mutations in the LRRK2 or SNCA genes have been linked to an autosomal dominant inheritance of PD.
• Mutations in PARK2, PARK7, or PINK1 display an autosomal recessive inheritance of PD.
• When SNCAIP or UCHL1 genes are involved, there is no clear pattern of inheritance.

Information on environmental factors

Homologs

Evolutionarily conserved homologs have been found in:
Mus musculus
Rattus norvegicus
Gallus gallus
Drosophila melanogaster
Caenorhabditis elegans

Animal models

Some animal models have been used to better understand the genes and proteins involved in PD.

In mice:
Weaver Mouse Gene

In Drosophila:
Drosophila PD model
Drosophila neurodegenerative disease models

Protein
Alpha-synuclein (AS), a product of the SNCA gene, has been associated with PD. This protein also has implications in Alzheimer Disease, and they may share similar mechanisms. Studies (1, 2, 3) of families with a history of PD have explored the role of AS. Their findings have revealed some evidence that AS is related to Parkinsonian conditions. However, this issue is controversial and is being researched further. Mouse models were used to explore the role of AS in Parkinson Disease. Giasson, B. I. et al. (2002) gave mutant and wild-type versions of human AS to transgenic mice. The mice with the mutant AS developed motor problems, while the mice with wild-type AS did not.

Further information about alpha-synuclein is available at:
The NCBI Genes and Disease site
Society for Neuroscience

Treatment
There is no cure for PD. However, there are treatments that reduce the severity of the symptoms. Because type of symptoms and responsivenesss to medication varies from one individual to the next, there are a variety of treatment options and combinations. The two main types of treatment are:

• Oral medications

Prescription medication is the most common form of treatment. There are several types of drugs. Levodopa, a dopamine precursor, is the most common form of medication. It is taken up by the brain and then transformed into dopamine. In addition to dopamine precursors, many PD patients take dopamine agonists, such as bromocriptine and ropinirole, which are directly involved in the substantia nigra, imitating dopamine.

• Surgery

Surgery is generally done as a last resort, for patients with severe symptoms or who are unresponsive to medication.
Palliodatomy is the lesioning of the globus pallidus. This helps treat rigidity, abnormal movements, tremors, freezing and falling.
Occasionally, a thalamotomy is performed to reduce tremors.
Deep Brain Stimulation, a relatively new technique, involves inserting electrodes in the brain to provide electrical stimulation. This fairly safe technique has been effective in helping PD patients control their motor movements.

Additional Info
Some helpful websites:
National Parkinson Foundation
The Michael J. Fox Foundation for Parkinson's Research
Parkinson's Disease Trials
OMIM Parkinson Disease overview article