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.
Nonetheless, some variants of specific genes could still contribute to sporadic Parkinson’s disease.
But simply put, for most cases of “sporadic Parkinson’s disease”, no specific genes can be found.
However, we can learn a lot from genetic causes of Parkinson’s disease, to better understand what mechanisms cause (sporadic) Parkinson’s disease.
Often, in genetic forms of the disease, mutations happen in genes encoding for proteins involved in protein accumulation/recycling, mitochondrial function, and handling of oxidative stress.
Below you can find the main mutations that cause Parkinson’s disease.
PARKIN (PRKN or 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 cell components (like mitochondria) that need to be broken down.
Ubiquitin is a small protein that serves as a flag for the breakdown of the substance it’s attached to. Parkin helps to put ubiquitin on mitochondria, tagging these mitochondria 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 these cells, contributing to Parkinson’s disease.
PINK1 (PARK6)
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 mitochondria, also called “mitophagy”).
When this tagging does not happen properly, the mitochondria are not broken down. Given mitochondria are vital for the energy production of cells, including brain cells, accumulation of damaged mitochondria leads to cellular dysfunction and cell death.
PARK7 (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 of alpha-synuclein protein plays an important role in Parkinson’s disease.
Synuclein alpha (SNCA or PARK1)
SNCA is the gene that encodes for alpha-synuclein.
Alpha-synuclein is the main protein that accumulates in brain cells, which plays an important 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 slightly different shape, so it accumulates faster or more easily.
GBA1 (glucocerebrosidase beta 1)
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 (GCase), a protein involved in the breakdown of sugary lipids (cerebrosides) and other molecules.
This enzyme is found in the lysosomes. Lysosomes 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 impairs lysosomal function.
When the lysosomes do not work properly, many (damaged) molecules and cell components start to accumulate in the cell given they are not properly broken down anymore by the lysosomes. Such accumulating substances can be alpha-synuclein protein and damaged mitochondria (R).
Damaged mitochondria and accumulation of alpha-synuclein hinder the proper functioning of cells, especially the dopaminergic cells which are the main cells that die off in Parkinson’s disease.
LRRK2 (PARK8)
LRRK2 (leucine-rich repeat kinase 2, also known as dardarin or PARK8) is a protein involved in genetic forms of Parkinson’s disease.
LRRK2 is a “kinase”. Kinases are proteins that put phosphate groups on many other proteins, activating or deactivating them.
Often in genetic Parkinson’s disease, this LRRkinase becomes too active.
When LRRK2 doesn’t function properly, this leads to many other proteins not being switched on or off. Many of these proteins are involved in autophagy (the breakdown of proteins) or mitochondrial maintenance.
For example, LRRK2 phosphorylates (deactivates) a protein called RAB, which plays an important role in the formation of cellular vesicles, which are involved in autophagy.
Therefore, mutations in this gene can negatively impact autophagy, or lead to mitochondrial problems and many other problems.
VPS35 (PARK19)
VPS35 is involved in mitochondrial function and endosomal trafficking (endosomes are little vesicles that cells use to transport substances inside them).
ATP13A2 (PARK9)
This gene encodes for a protein found in the membranes of lysosomes, the little vesicles in our cells that break down waste materials, including proteins and mitochondria.
OTHER PARKINSON GENES
Many other genes have been discovered that can cause Parkinson’s disease, such as SYNJ1, DNAJC6, FBX07, PLA2G6, and others.
Many more genes continue to be discovered.
