Heredity Genetics of Parkinson's Disease

Heredity of Parkinson's Disease

What is Parkinson's Disease?

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in humans, Alzheimer’s dementia being the first. Parkinsonism and paralysis agitans are two other names (but rarely used today) of PD (Morrison, 143). This disease mainly occurs in people over the age of 65, affecting about 1.8% of the world-wide population (Bogaerts, 129, Belin, 1377), and the development of risk increases with time (Vila, S58). It affects approximately 130 out of 100,000 people per year, and it is more common to human males than females. It was first described in 1817 (Morrison, 143) and it wasn’t until recently that this disease became known to be linked to genetics. The pathways for Parkinson’s disease include both environmental and genetic factors, and the resulting symptoms are dreadful. In attempt to cure this disease, research is being done in many areas, including pharmacological therapy, psychological placebo treatments, and stem cell replacement technique.

What Causes PD?

Both environmental and mutations in genes contribute to the development of Parkinson’s disease (PD). Studies have shown that exposure to certain chemicals can develop the symptoms of PD in humans. Several genetic mutations, whether inherited and or developed sporadically, are found to be responsible for the cause of PD. Studies so far show that gene mutations in Parkin, PINK1, and LRRK2 are associated with increased damages to dopaminergic neurons which can result in PD (Bogaerts, 129). This study shows a relation with PD’s characteristic - the degeneration of dopamine neuron and depigmentation of the substantia nigra along with neuron loss in the ventral tegmental area and locus coeruleus (Belin).

Is Parkinsons Purely Genetic? NOPE!

Environmental chemicals have the ability to reproduce symptoms of Parkinson’s disease. Bogaerts found that drug abusers that extensively consumed 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed symptoms of PD. He explains that MPTP’s metabolite, 1-methyl-4-phenylpyridinium (MPP+), is transported into DAergic neurons by the dopamine transporter. MPP+ then enters mitochondria within these neurons and selectively inhibits mitochondrial respiration at complex I of the electron transport chain. This process is likely to impair the production of dopamine neuron, thus damaging the body’s ability to use the nerves. In addition, chronic mixture of rotenone (another highly selective complex I inhibitor) have also been found to produce behavioural and neuropathological features in rats. These symptoms produced by the exposure to MPTP and rotenone showed that PD can be caused by environmental influences (129).

Dysfunctional Mitochondria May Be Another Cause

Besides the harmful effects of chemicals, oxidative stresses by dysfunctional mitochondria may be one of the contributors for PD. Simply put, mitochondria is energy-producing mechanism (organelle) in the cell.

Oxidative stress is characterized by a high level production of reactive oxygen species (ROS) that harm cells, proteins, lipids and DNA as well as having a lack of antioxidants that protect them from the ROS (Bogaerts, 130). ROS is generated as a by-product of phosphorylation in the mitochondria, and studies show that it may cause damage to dopamine neurons in the brain (130). Oxidation in the dopaminergic neurons in the substantia nigra may result in fatal damage to the cells (130). Devi states that antioxidant level is decreased in the elderly (143). This will expose dopamine-producing neurons in the brain to a greater risk of oxidative damage; it may explain why Parkinson’s disease occurs more frequently in people over the age of 60.

Heredity Factors of Parkinson's Disease - "Parkin" Gene

The mutations in parkin can cause autosomal recessive early onset PD. Parkin is located in the proliferating cells in the mitochondria and studies suggests its role in “mitochondrial biogenesis by regulating both transcription and replication of mtDNA” (Bogaerts, 135). Mutations in parkin showed a decreased quantity of proteins that are involved in mitochondrial respiratory chain activity and protection against oxidative stress (135). In addition, cells in drosophila that contained surplus of parkin expression showed that it was protected from ceramide-mediated cell death “by delaying mitochondrial swelling” (135). In humans, parkin over-expression protected cells from apoptosis, and also decreased cellular ROS levels. Additionally, a combination of malfunctioning mitochondria, oxidative stress, and parkin mutation could lead to haploinsufficiency (lack of a haploid) in sporadic patients with heterozygous parkin mutations (136). The mutations in parkin gene cause harm the protective system against oxidative damage, which can result in PD.

Heredity Factors of PD - "PINK1" gene

Mutations in PTEN-induced putative kinase 1 (PINK1) gene was found to be associated with PD. PINK1 is a tremor suppressor with a “serine-threonine kinase and a mitochondrial targeting motif, making it prone to accumulate in the intermembranous space of mitochondria” (Belin, 1380). Heterozygous PINK1 were reported to be enriched threefold in sporadic PD patients compared to control individuals (non-affected by PD), and it was shown to cause late-onset PD (Bogaerts, 136). Study shows that “RNA interference-mediated inactivation of the PINK1 homologue in Drosophila resulted in progressive loss of [dopaminergic neurons]” (136). The inactivation of PINK1 was associated with the deaths of neurons due to its vulnerability to oxidative damage. This study suggested that PINK1 had protective roles in the neurons; thus, the mutations in this gene may cause loss of dopamine, resulting in loss of nerve control.

Heredity Factors - "LRRK2" Gene

A single mutation in leucine-rich repeat kinase 2 (LRRK2), G2019S, is one of the most common causes of autosomal dominant late onset PD. G2019S alone is responsible 5-6% of all familial (inherited) PD and in 1-2% of all sporadic (non-inherited) PD, it is considered to be one of the most direct evidences of the cause of this disease (Bonifati). In North African Arabs population, the G2019S mutation frequency is as high as 41% (Belin, 1380). One of the novel studies showed that patients who carried G2019S mutation had a 17.6 times greater risk of developing PD (Bonifati).LRRK2 are expressed in the dopamine target areas, striatum and frontal cortex (Bogaerts, 136), and missense mutations (single nucleotide mutation) in this gene are found to be involved with the neuronal cell degenerations in SH-SY5Y cells (neuroblastoma cells) (137). The mutation in LRRK2 also shows an involvement with the neuronal cell degeneration.

Symptoms of Parkinson's Disease

Both physiological and mental symptoms can arise in patients with Parkinson’s disease. Physical symptoms include muscle rigidity, bradykinesia, impaired balance, tremor at rest, and decreased mobility (Morrison, 143-44, Belin,1377). Tremor is characterized by the rough back and forth movements of thumb and forefingers, about 4 cycles per second which is not very fast. Tremor usually occurs when the patient is at rest, and it may start from one side and spread to affect other parts of the body. Muscle rigidity and loss of mobility may begin with reduced ability to blink and move other facial muscles, which will eventually spread to other parts. This is shown by the dull (non-smiling or non-frowning) facial expressions, monotone voice, and irregular swinging of the arms when walking in PD patients. In addition, they also have difficulty initiating movements, such as taking a first step when walking; PD patients may have to intentionally fall forward in order to force their first step (appears as an effort to prevent falling over).

Patients with advanced (severe) disease, they may show symptoms such as forwardly bent spine, drooped shoulders, and flexed forearms at the elbows. They may also show akinesia (loss of voluntary muscle control) and have a hard time performing normal daily activities such as dressing up, eating and swallowing, which may result in drooling (Morrison, 143-44).

Acquiring some of these physical disabilities can lead to mental stresses and show symptoms like anxiety, depression, withdrawal, loss of interest, weakness and dementia (memory disorders, personality changes, and impaired reasoning) (Morrison, 144-45). Generally, the symptoms of PD are the loss of voluntary movements which can lead to emotional stress that may affect mental abilities.

How to Treat Parkinson's Disease?

Currently, psychological and physical treatment techniques are used when treating Parkinson’s disease patients. PD is currently without a complete cure – treatments may be able to lessen the symptoms but cannot completely cure the disease. Pharmacological therapy produced devastating side-effects in patients, thus new treatment methods are currently being researched (Trzaska, 99). One research shows that symptoms of PD can be eased when patients strongly believe that they can be cured by a treatment method. Niemi found that “placebos can help not only to alleviate illnesses with an obvious psychological component, such as pain, depression, and anxiety, but also to lessen the symptoms of Parkinson’s disease.” When patients believe in the effectiveness of a treatment that is actually a sham, this belief can become a cure to improve the symptoms of Parkinson’s disease.

Another research that is currently being done may be the best possible physical treatment technique so far – the stem cell replacement technique. Doctors are using stem cells and its ability to derive dopamine neurons, and attempting to transplant them into the affected area of the brain; they are used as a substitute for the degenerated ones (Trzaska, 99). Transplantation of stem cell-derived dopamine neurons demonstrated potential benefit in neuro-regeneration when tested in animals (99). However, despite its possible potential curing ability, brains of humans and other animals are quite dissimilar and thus it is still a difficult and unperfected treatment method to cure PD(106). The current knowledge and technology is insufficient and thus, a further study and research is required in order to make an excellent cure.

Conclusion

Parkinson’s disease is a neurodegenerative disorder that causes loss of motor control in patients. Studies showed that PD does not necessary have to be inherited in order to affect individuals; environmental factors, such as harmful chemicals and drugs, also place a high risk in developing PD symptoms. Symptoms are characterized by loss of voluntary movement, primarily due to the deaths of dopaminergic neurons and a lack of defence against oxidative stress (caused by dysfunctional mitochondria) in the brain. To cure this disease, pharmacological therapies were initially used, but due to its harmful side-effects, new researches are currently being done. The new researches include psychological treatments (the use of placebos) and transplantation of stem cells in attempt to regenerate neurons. None of the treatment techniques are perfect, and requires a further research and study in order to create a desired cure.

Works Cited

Belin, Andrea C., and Marie Westerlund.. "Parkinson’s disease: A genetic perspective." FEBS Journal 275.7 (Apr. 2008): 1377-1383. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 6 Apr. 2009.

Bogaerts, V., J. Theuns, and C. Van Broeckhoven. "Genetic findings in Parkinson’s disease and translation into treatment: a leading role for mitochondria?." Genes, Brain & Behavior 7.2 (Mar. 2008): 129-151. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 6 Apr. 2009

Bonifati, Vincenzo. "Parkinson's Disease: The LRRK2-G2019S mutation: opening a novel era in Parkinson's disease genetics." European Journal of Human Genetics 14.10 (Oct. 2006): 1061-1062. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 6 Apr. 2009

Devi, P. Uma, and P. Chinnaswamy.. "Age and Gender Related Changes in Free Radical Pathology and Antioxidant Defense in Schizophrenia." Asian Journal of Biochemistry 3.3 (Sep. 2008): 143-152. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 6 Apr. 2009

Morrison, James. When psychological problems mask medical disorders. New York: Guilford Publications, 1997.

Niemi, Maj-Britt. "Cure in the Mind." Scientific American Mind 20.1 (Feb. 2009): 42-49. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 6 Apr. 2009

Trzaska, Katarzyna A., and Pranela Rameshwar.. "Current Advances in the Treatment of Parkinson's Disease with Stem Cells." Current Neurovascular Research 4.2 (Apr. 2007): 99-109. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 7 Apr. 2009

Vila, Miquel, and Serge Przedborski.. "Genetic clues to the pathogenesis of Parkinson's disease." Nature Medicine 10 (02 July 2004): S58-S62. Academic Search Complete. EBSCO. [CUC Library], [Lacombe], [AB]. 6 Apr. 2009

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