Ever wonder what genes are linked to Parkinson’s disease?
There are over 15 genes identified that are linked to Parkinson’s disease. Research shows that mutation in some of these genes can directly cause Parkinson’s symptoms, while in others it may increase the risk of developing the disease. Here, we discuss those genes and the type of Parkinson’s disease that they cause when mutated.
Parkinson’s disease (PD) is a neurodegenerative disorder that has affected more than 10 million people worldwide. The most common symptoms include tremor, muscle stiffness, slowness of movements, difficulty walking, and balance problem. These symptoms usually start gradually and progress over time.
The majority of Parkinson’s cases are sporadic; meaning that the disease develops with no apparent cause. However, 15% are those where genetics play a role. And as research on the genetics of Parkinson’s progresses, researchers are uncovering defective genes that cause this disease. They have already identified more than a dozen genes that are linked to Parkinson’s disease. Among these genes, seven are the main ones and have gotten more attention. Mutations in these genes cause PD that are divided into two categories:
- Autosomal dominant PD
- Autosomal recessive PD
1. Autosomal dominant PD
A single copy of the defective autosomal gene (a gene that is located on autosomal chromosomes) is enough to cause this form of PD. It develops when a person gets the defective gene from only one parent. In most cases, one of the parents can also have the disease.
The two main genes that are known to cause this form of PD include SNCA and LRRK2.
This gene makes a small protein called alpha-synuclein. The alpha-synuclein protein is mainly expressed in the brain and its exact function is still unknown. In the brain, it is found at the tip of neurons, where it may help in the release of chemical messengers.
Mutation in the SNCA gene causes abnormal structures in the neuron. These abnormal inclusions are known as Lewy body, which are the characteristics of PD. SNCA gene mutations account for a tiny fraction of PD in the general population. The patients show typical signs of PD and are under the age of 50.
This gene is translated into a large protein called leucine-rich repeat kinase 2 (LRRK2), also called dardarin. The LRRK2 protein is rich in leucine amino acids, and that’s the reason why it is named leucine-rich repeat kinase 2. Although the exact function of this protein is not known, it interacts with many other proteins essential for various cellular functions.
Mutations in the LRRK2 gene are considered to be the most frequent cause of autosomal dominant PD. To date, over 100 mutations have been identified that are linked to PD. These mutations often cause defects in the structure and functions of LRRK2 protein. The clinical features are similar to the typical PD and appear after the age of 50.
2. Autosomal recessive PD
This form of PD develops when a person gets two defective autosomal genes, one from each parent. Often, parents do not show any signs of the disease in their life.
Following are the main genes causing this form of PD.
This gene is responsible for making the PINK1 protein, which is a well-known PD-related protein. The PINK1 protein is primarily found in the mitochondria, which are the sites for energy production inside the cell. There, it helps to preserve mitochondrial function under stress conditions. The dysfunction of PINK1 protein has been shown to cause the abnormal release of dopamine inside the brain. Dopamine is a chemical messenger in the brain and its deficiency is believed to be the main reason of developing Parkinson’s symptoms.
To date, over 70 different mutations have been identified in the PINK1 gene that are associated with PD. People carrying mutations in this gene develop the disease signs either in their 40s or after. Clinical examination has shown that they present signs similar to those that appear in the early stage of the PD.
This was the first gene associated with the autosomal recessive form of PD. It forms a protein called Parkin. This protein is mainly found in the cytoplasm but recruits to mitochondria under stressed conditions where it interacts with the above-mentioned PINK1 protein. The interaction between the two proteins results in a pathway that helps to get rid of damaged mitochondria from the cell.
Several mutations have been identified in the PARKIN gene that are known to cause PD. Some of these cause abnormal changes in the structure of Parkin protein, others disrupt the ability of Parkin protein to bind with other proteins. These mutations are responsible for the majority of autosomal recessive early-onset cases of PD, typically starting at the age of 45. In addition to the typical symptoms, the patients usually show dystonia, pronounced daily fluctuation, and sleep problems.
This gene provides instruction for making a protein called DJ-1. DJ-1 protein is one of the key players in the antioxidant defense mechanism of the cell. Its main function is to provide protection to cells from the damage of oxidative stress. Oxidative stress is an abnormal condition that develops when the antioxidant defense system of the cell fails to fight against oxygen-containing molecules called reactive oxygen species. These molecules, when produced in excess, are known to cause damage to vital components of the cell. Researchers believe that oxidative stress is the key factor in developing Parkinson’s disease changes in the brain.
Like other autosomal recessive PD genes, mutations in PARK7 cause early-onset PD. Most patients who carry mutations in this gene show the disease signs at the age of 50 or before. It is not yet clear how mutations in the PARK7 gene cause changes in the brain that lead to PD.
This’s a relatively new PD-related gene that makes a protein called ATP13A2 (ATPase Cation Transporting 13A2). Researchers are examining in detail the activity, localization, and binding partners of ATP13A2 protein. The data collected so far suggest that it is required for the normal function of the lysosome. Lysosomes are spherical structures that are responsible for the destruction of cellular components that are no longer needed.
Mutations in the ATP13A2 gene cause a rare form of PD known as Kufor-Rakeb syndrome, which is named after a district in Jordan where it was first discovered. It affects people at a young age. The youngest patient reported to be the victim of mutation in this gene was a 12 years old Lithuanian boy. Patients show abnormal eye movement and dementia, along with other typical signs of PD.
This gene carries information for making a protein called iPLA2β (calcium-independent phospholipase A2 beta enzyme). The iPLA2β protein is responsible for the correct signaling of calcium inside the cell. It is also important for the proper functioning of mitochondria and cell membrane.
The link of PLA2G6 gene mutation with PD was first reported in 2010. Since then, several mutations have been found in this gene that are known to cause an autosomal recessive form of PD. The majority of patients carrying mutations in this gene are reported to develop disease signs at early adulthood. Although the precise mechanism of its mutation in PD is unknown, brain analysis has shown that it causes abnormal changes in the alpha-synuclein protein (mentioned above) in the brain region involved in PD. In addition, iron accumulation has also been noticed in the brains of some patients.
Disclaimer: The information shared here should not be taken as medical advice. The opinions presented here are not intended to treat any health conditions. For your specific medical problem, consult with your health care provider.