Only around 10% of cases of Parkinson’s disease are caused by genetic mutations. Around 90% of Parkinson’s disease is called “sporadic” Parkinson’s disease, meaning there is no single genetic mutation that causes the disease.
However, we can learn a lot from these genetic causes of Parkinson’s disease, especially in relation to what could cause sporadic Parkinson’s disease.
We see that often in these genetic forms of the disease, mutations happen in genes involved in mitochondrial function, protein accumulation/recycling, and handling of oxidative stress.
Below you can find some well-known mutations that cause Parkinson’s disease.
PRKN (PARK2)
Mutations in this gene are the most common cause of early onset Parkinson’s disease.
PRKN (also called PARK2) is the gene that encodes for the parkin protein. Parkin puts ubiquitin on substances that need to be broken down in the cell.
Ubiquitin is a small protein that serves as a flag for the breakdown of the substance it’s attached to. Specifically, parkin helps to put ubiquitin on so these mitochondria are “tagged” to be broken down.
Mitochondria are important components of the cell that produce energy for the cells.
Defects in parkin lead to the accumulation of damaged mitochondria in neurons, which impairs the energy production in cells, contributing to Parkinson’s disease.
PINK1
Mutations in this gene are the second most common cause of early onset Parkinson’s disease.
PINK1 works together with the parkin protein to “tag” the mitochondria for breakdown (via a process called “autophagy” of the mitochondria, also called mitophaghy”).
When this tagging cannot happen properly, the mitochondria are not broken down properly. Given mitochondria are vital for the energy production of cells, including brain cells, this leads to cellular dysfunction and cell death.
PARK7 (also called protein deglycase DJ-1)
Mutation in this gene can also cause early-onset parkinsonism. PARK7 is a protein that protects cells against oxidative stress.
It also functions as a “chaperone” for alpha-synuclein, meaning it gently sticks to this protein and protects the alpha-synuclein from aggregating.
Clumping together of alpha-synuclein plays an important role in Parkinson’s disease.
SNCA
SNCA is the gene that encodes for alpha-synuclein. Alpha-synuclein is the protein that accumulates in brain cells, which plays a role in the death of brain cells in Parkinson’s disease.
Often, mutations in the SNCA gene cause the alpha-synuclein protein to have a different shape, so it accumulates faster or more easily.
GBA1
It’s estimated that around 10% of people with genetic Parkinson’s disease carry mutations in this gene.
The GBA gene encodes for the glucocerebrosidase enzyme (also called GCase), a protein involved in the breakdown of specific sugars.
This enzyme is found in the lysosomes, which are specific compartments in the cell specialized in the breakdown of many substances, ranging from sugars and protein to mitochondria and other large cell components.
It’s hypothesized that malfunctioning glucocerebrosidase enzymes could impair lysosomal function.
When the lysosomes do not work properly, many (damaged) molecules and cell components could start to accumulate in the cell given they are not properly broken down anymore, such as the alpha-synuclein protein and damaged mitochondria (R).
Damaged mitochondria and accumulation of alpha-synuclein impeded the proper functioning of cells, especially the dopaminergic cells that die in Parkinson’s disease.
LLRK2 (or PARK8)
LLRK2 (leucine-rich repeat kinase 2, also known as dardarin or PARK8) is a protein involved in genetic forms of Parkinson’s disease.
Mutations in this gene can negatively impact autophagy, or lead to mitochondrial problems.
VPS35
VPS35 is involved in mitochondrial function and endosomal trafficking (endosomes are little vesicles that cells use to transport substances inside them).
Many other genes have been discovered that can cause Parkinson’s disease.
