# Causes of Parkinson's disease

Parkinson's disease (PD) is a complicated neurodegenerative disease that progresses over time and is marked by bradykinesia, tremor, and stiffness. As the condition worsens, some patients may also experience postural instability. Parkinson's disease (PD) is primarily caused by the gradual degeneration of dopaminergic neurons in the region known as the substantia nigra along with other monoaminergic cell groups throughout the brainstem, increased activation of microglia, and the build-up of Lewy bodies and Lewy neurites, which are proteins found in surviving dopaminergic neurons.
Because the etiology of about 80% of PD cases is unknown, they are classified as idiopathic, whereas the other 20% are thought to be genetic. PD risk is increased by variations in the genetic mix of specific genes. Research has indicated that the risk of Parkinson's disease (PD) is increased by mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2), Parkinson's disease-associated deglycase (PARK7), PRKN, PINK1, or SNCA (alpha-synuclein).
Exposure to pesticides, metals, solvents, and other toxicants has been studied as a factor in the development of Parkinson's disease.

## Genetic factors

Traditionally, Parkinson's disease has been considered a non-genetic disorder. However, around 15% of individuals with PD have a first-degree relative who has the disease. At least 5–15% of cases are known to occur because of a mutation in one of several specific genes, transmitted in either an autosomal-dominant or autosomal-recessive pattern.
Mutations in specific genes have been conclusively shown to cause PD. A large number of these genes are linked to translation. Genes which have been implicated in autosomal-dominant PD include PARK1 and PARK4, PARK5, PARK8, PARK11 and GIGYF2 and PARK13 which code for alpha-synuclein (SNCA), UCHL1, leucine-rich repeat kinase 2 (LRRK2 or dardarin) (LRRK2 and Htra2 respectively Genes such as PARK2, PARK6, PARK7 and PARK9 which code for parkin (PRKN), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2 respectively have been implicated in the development of autosomal-recessive PD Furthermore, mutations in genes including those that code for SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD. The most extensively studied PD-related genes are SNCA and LRRK2.
At least 11 autosomal dominant and nine autosomal recessive gene mutations have been implicated in the development of PD. The autosomal dominant genes include SNCA, PARK3, UCHL1, LRRK2, GIGYF2, HTRA2, EIF4G1, TMEM230, CHCHD2, RIC3, and VPS35. Autosomal recessive genes include PRKN, PINK1, DJ-1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, and VPS13C. Some genes are X-linked or have unknown inheritance pattern; those include USP24, PARK12, and PARK16. A 22q11 deletion is known to be associated with PD. An autosomal dominant form has been associated with mutations in the LRP10 gene.

### SNCA gene

The role of the SNCA gene is significant in PD because the alpha-synuclein protein is the main component of Lewy bodies, which appear as a primary biomarker in the disease. Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD. Level of alpha-synuclein expression correlates with disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication. Missense mutations in SNCA are rare. On the other hand, multiplications of the SNCA locus account for around 2% of familial cases. Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.

### LRRK2 gene

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain. A significant number of autosomal-dominant Parkinson's disease cases are associated with mutations in the LRRK2 gene Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number. Mutations in PINK1, PRKN, and DJ-1 may cause mitochondrial dysfunction, an element of both idiopathic and genetic PD. Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia. This could be relevant in PD cases associated with dementia.

### GBA gene

Mutations in GBA are known to cause Gaucher's disease. Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results. Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism. Incidentally, both gain-of-function and loss-of-function GBA mutations are proposed to contribute to parkinsonism through effects such as increased alpha-synuclein levels. In patients with Parkinson's disease, the OR for carrying a GBA mutation was 5·43 (95% CI 3·89–7·57), confirming that mutations in this gene are a common risk factor for Parkinson's disease.

### Genes underlying familial Parkinson's disease

Genes underlying familial PD :
| HGNC symbol | Gene | Locus | Function | Mutations | Clinical Presentations | Neuropathology | Age at onset | Inheritance |
| PARK1/PARK4 | SNCA (α-synuclein) | 4q21 | Unknown synaptic function | Duplications | Idiopathic PD; some postural tremor; slow progression | LBs | Mid 20s – 30 | Dominant |
| | SNCA | 4q22 | instructions for making a small protein called alpha-synuclei may play a role in maintaining supply of synaptic vesicles in presynaptic terminals; may regulate release of dopamine | Triplications | PD (Parkinson's Disease); PD with dementia;diffuse LBs disease;aggressive course; can develop cognitive dysfunction, autonomic failure, and myoclonus | LBs and Lewy neurites; ± glial inclusions; hippocampal CA2 and CA3 loss | Mid 20s – 30s | |
| | | | | A53T, A30P E46K | Idiopathic PD; early on setparkinsonism and diffuse LBs | LBs and LNs; ± tau inclusions; amyloid plaques | 30–60 | |
| PARK2 | Parkin | | E3 ubiquitin ligase | 200+ possible mutations including: - Inactivating somatic mutations - Frequent intragenic deletions | Early on set Parkinsonism; slow progression PD | variable presence of LBs | Juvenile to 40 | Recessive |
| PARK5 | UCHL1 | | deubiquitinating enzyme | Missense: Ile93Met | PD; late on set parkinsonism | Unknown; various abnormal protein aggregations | 30–50 | Dominant |
| PARK6 | PINK1 | | mitochondrial Ser-Thr Kinase | 40+ mutations -Mostly point mutations -Deletions on C-terminus Kinase domain | Parkinsonism | Unknown | 30–50 | Recessive |
| PARK7 | DJ-1 | | oxidative stress response? | -10 point mutations including C46A, C53A, C106 & WT regions - Large deletion in L166P | Early onset Parkinsonism | Unknown | 20–40 | Recessive |
| PARK8 | LRRK2 (dardarin) | 12q12 | unknown protein kinase | G2019S most common | late-onset Parkinson's Disease | Diffuse LBs; LNs; ± tau inclusions; ± amyloid plaques | 40–60 | Dominant |

## Environmental factors

Exposure to pesticides, metals, solvents, and other toxicants has been studied as a factor in the development of Parkinson's disease. No definitive causal relationship has yet been established. Recent studies also reveal that individuals that sustain mild head injuries (concussions) also have an increased risk of acquiring the disease. As discussed below, exercise and caffeine consumption are known to help decrease the risks of acquisition.

### Pesticides

Evidence from epidemiological, animal, and in vitro studies suggests that exposure to pesticides increases the risk for Parkinson's disease. One meta-analysis found a risk ratio of 1.6 for ever being exposed to a pesticide, with herbicides and insecticides showing the most risk. Rural living, well-drinking, and farming were also associated with Parkinson's, which may be partly explained by pesticide exposure. These factors are pertinent to many communities, one of them being South Asian populations. Organochlorine pesticides (which include DDT) have received the most attention, with several studies reporting that exposure to such pesticides is associated with a doubling of risk for Parkinson's.
Carbon disulfide is a risk factor, and has been identified in industrial worker case studies and has induced parkinsonism in mice. It is mainly used in the manufacture of viscose rayon, cellophane film, rubber and carbon tetrachloride.

### Metals

Lead, which was used in gasoline until 1995 and paint until 1978, is known to damage the nervous system in various ways. A few studies have found that people with high levels of lead in their body had twice the risk of Parkinson's disease. Epidemiological studies on lead, however, have found little evidence for a link with Parkinson's. Iron has been implicated in the etiology of Parkinson's disease, but there is no strong evidence that environmental exposure to it is associated with Parkinson's.

### Head injuries

A 2012 study suggests that players in the National Football League are three times more likely to die from neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, than the general US population. A 2018 study found 56% increase in risk of Parkinson's disease among US military veterans suffered traumatic brain injury.

### Exercise

While many environmental factors may exacerbate Parkinson's disease, exercise is considered to be one of the main protective factors for neurodegenerative disorders, including Parkinson's disease. The types of exercise interventions that have been studied can be categorized as either aerobic or goal-based. Aerobic exercise includes physical activity that increases the heart rate. Aerobic exercise is beneficial to the overall brain through mechanisms that promote neuroplasticity, or the rewiring of the brain circuitry. Goal-based exercises are often developed with the guidance of a physical therapist to use movement to improve motor task performance and enhance motor learning. While exercise has consistently been shown to be beneficial, the optimal interventional benefit is still being researched.

### Caffeine consumption

Smokers and nonsmokers with different rates of caffeine consumption were monitored for their susceptibility to PD. The results indicate that higher coffee/caffeine intake is associated with a significantly lower incidence of PD and that this effect appeared to be independent of smoking.

### Dietary Factors

Emerging research suggests that diet may influence the risk of developing Parkinson's. A 2023 study found that adherence to a Western dietary pattern—characterized by high consumption of red and processed meats, fried foods, high-fat dairy products, and refined grains—is associated with an increased risk of Parkinson's. Individuals with the highest adherence to this dietary pattern had significantly higher odds—approximately seven times—of developing the disease. Conversely, diets rich in fruits, vegetables, whole grains, and lean proteins have been associated with a reduced risk of Parkinson's, potentially offering protective benefits. Further research is needed to establish causality and better understand the mechanisms underlying these associations.

## Environmental-Genetic factors
### Polymorphism of CYP2D6 gene and pesticide exposure

The CYP2D6 gene is primarily expressed in the liver and is responsible for the enzyme cytochrome P450 2D6. A study showed that those who had a mutation of this gene and were exposed to pesticides were twice as likely to develop Parkinson's Disease; those that had the mutation and were not exposed to pesticides were not found to be at an increased risk of developing PD; the pesticides only had a "modest effect" for those without the mutation of the gene.