Parkinson’s disease (PD) is a progressive disorder of the nervous system resulting from the loss of dopamine-producing neurons in the brain’s substantia nigra region. The recognizable features of the condition include a resting tremor, muscle rigidity, and bradykinesia (slowness of movement). While the disease is often associated with aging and environmental exposures, research shows that genetic factors play a role in its development and progression. The genetic contribution is complex, ranging from rare, direct causes to common factors that increase susceptibility when combined with other influences.
Understanding Genetic Contribution
The genetic contribution to Parkinson’s disease is divided into familial and sporadic cases. Familial PD accounts for a small minority (5% to 10%) of all diagnoses. These cases are characterized by a clear inheritance pattern, often caused by a single, highly penetrant gene mutation. Inheriting the mutation makes the development of the disease highly likely.
The vast majority of diagnoses (90% to 95%) are classified as sporadic Parkinson’s disease, meaning there is no clear family history or single genetic cause. The disease results from the cumulative effect of multiple low-risk genetic factors, known as susceptibility genes, interacting with environmental exposures. While a single gene may cause the disease in some, many small genetic variations increase the overall risk for the majority of people.
Key Genes in Inherited Parkinson’s
The most direct genetic link to Parkinson’s disease involves highly penetrant genes that, when mutated, almost guarantee the condition’s development. The first gene identified was SNCA (Alpha-synuclein), which instructs cells to make the alpha-synuclein protein. Mutations or duplications in SNCA lead to an overproduction or misfolding of this protein, causing it to clump and form the characteristic Lewy bodies found in the brains of people with PD.
LRRK2 (Leucine-rich repeat kinase 2) is the most common cause of autosomal dominant PD. A mutation in just one copy of the LRRK2 gene is often enough to cause the disease, though its penetrance is incomplete, meaning not every carrier will develop symptoms. This gene produces a protein that acts as a kinase, an enzyme that adds phosphate groups to other proteins, and its mutation often results in excessive activity that is toxic to neurons.
In contrast, the PRKN (Parkin) gene is the most common cause of early-onset Parkinson’s disease, typically inherited in an autosomal recessive pattern. This means a person must inherit a mutated copy from both parents. PRKN makes the Parkin protein, which functions as an E3 ubiquitin ligase, a component of the cell’s waste disposal system. Loss-of-function mutations impair the cell’s ability to clear out damaged proteins, leading to neuronal dysfunction and death.
Common Genetic Risk Factors
While the genes causing inherited PD are highly penetrant, the majority of genetic risk comes from susceptibility factors that subtly increase a person’s likelihood of developing the disease. Genome-Wide Association Studies have pinpointed approximately 90 genetic risk variants across 78 genomic regions that contribute to sporadic PD.
The most significant genetic risk factor is the GBA (Glucocerebrosidase) gene, with variants found in 5% to 15% of all PD patients. Although inheriting two severe mutations in GBA causes Gaucher disease, inheriting just one copy of a GBA variant significantly increases the risk of developing Parkinson’s. This single-copy variation often leads to an earlier age of onset and more frequent cognitive impairment compared to non-carriers.
Other variants in genes like MAPT (Microtubule-Associated Protein Tau) and GAK (Cyclin G-Associated Kinase) also confer risk for sporadic PD. These susceptibility genes act as genetic vulnerabilities that, when combined with age and environmental elements, push the individual past the threshold for developing the neurodegenerative process.
Cellular Pathways Affected by Genetic Mutations
Genetic mutations disrupt processes necessary for the survival of dopamine-producing neurons. One common functional consequence is the protein misfolding and aggregation pathway, focusing on alpha-synuclein. Mutations in SNCA directly cause the alpha-synuclein protein to misfold and clump together into insoluble structures called Lewy bodies, which are the pathological hallmark of Parkinson’s disease. This accumulation is toxic to the cell and impairs its function.
A second pathway affected is mitochondrial dysfunction, which involves the cell’s energy production and quality control systems. Genes like PRKN and PINK1 are directly involved in a process called mitophagy, where damaged mitochondria (the cell’s powerhouses) are identified and cleared out. Mutations in these genes impair this cleanup process, leading to the accumulation of faulty mitochondria. This results in oxidative stress and an energy deficit that ultimately causes the neuron to die.
Finally, the lysosomal and autophagy pathways, which are the cellular waste disposal and recycling centers, are frequently impaired by PD-linked genes. The GBA gene produces the enzyme glucocerebrosidase (GCase) that works in the lysosome to break down fatty substances. A deficiency in GCase activity, caused by a GBA mutation, leads to lysosomal impairment and the failure to properly clear out alpha-synuclein, causing it to accumulate. Mutations in LRRK2 may also interfere with this waste disposal mechanism, linking multiple genetic causes to a common mechanism of neuronal death.