Causes of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that progresses over time, marked by bradykinesia (slowed movements), tremor (rhythmic shaking), and stiffness, that affects approximately 10 million people worldwide.[1] As the condition worsens, some patients may also experience postural instability where one finds it difficult to balance and maintain upright posture.[2]

Parkinson's disease (PD) is primarily caused by the gradual degeneration of dopamine producing neurons in a brain region called the substantia nigra and other related cell groups in the brainstem.[3] This process is accompanied by increased activation of microglia, the brain's immune cells, and the build-up of Lewy bodies and Lewy neurites, which are clumps of proteins found in the surviving dopaminergic neurons.[4]

About 20% of cases appear to have a genetic factor. PD risk is increased by variations in the genetic mix of specific genes.[5] 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).[6][7]

The remaining 80% of PD cases are classified as idiopathic, meaning their cause is unknown. While not attributable to a single identifiable cause, there are risk factors and protective factors that relate to Parkinson's disease. Exposure to pesticides, metals, solvents, and other toxicants has been studied as a factor in the development of Parkinson's disease. Traumatic brain injury and Type 2 diabetes have also been identified as risk factors. Exercise, caffeine consumption. and diets rich in fruits, vegetables, whole grains, and fish are associated with lower risk of PD.

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.[8] 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.[9]

Mutations in specific genes have been conclusively shown to cause PD, a large number of which are linked to translation.[10][11] 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.[9][12] 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[9][13][14]

Mutations in genes including those that code for SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD.[15] 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.[16] The most extensively studied PD-related genes are LRRK2[17] and SNCA.[18]

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, transmitting to males and females, or have an unknown inheritance pattern; those include USP24, PARK12, and PARK16. A 22q11 deletion is known to be associated with PD.[19][20]

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.[9][21][22] 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.[9][23] Level of alpha-synuclein expression correlates with disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication.[24][25] Missense mutations in SNCA are rare.[9][23] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[9][23] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[9][25]

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.[16] A significant number of autosomal-dominant Parkinson's disease cases are associated with mutations in the LRRK2 gene.[26] These mutations 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.[9][16] There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.[9] Mutations in PINK1, PRKN, and DJ-1 may cause mitochondrial dysfunction, an element of both idiopathic and genetic PD.[24] Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia.[27] This could be relevant in PD cases associated with dementia.[27]

GBA gene

Mutations in GBA are known to cause Gaucher's disease.[9] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.[28] Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism.[29] 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.[29] 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.[29]

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[30] SNCA[31] (α-synuclein) 4q21[32] Unknown synaptic function Duplications Idiopathic PD; some postural tremor; slow progression LBs Mid 20s – 30 Dominant
SNCA 4q22[32] instructions for making a small protein called alpha-synuclei[33]

may play a role in maintaining supply of synaptic vesicles in presynaptic terminals;

may regulate release of dopamine[33]

Triplications PD (Parkinson's Disease); PD with dementia;diffuse LBs disease;aggressive course; can develop cognitive dysfunction, autonomic failure, and myoclonus[34] LBs and Lewy neurites; ± glial inclusions; hippocampal CA2 and CA3 loss Mid 20s – 30s
A53T, A30P E46K[9][35] Idiopathic PD; early onset Parkinsonism and diffuse LBs LBs and LNs; ± tau inclusions; amyloid plaques 30–60
PARK2[30] Parkin[36] E3 ubiquitin ligase[37] 200+ possible mutations including:[37]

- Inactivating somatic mutations

- Frequent intragenic deletions

Early onset Parkinsonism; slow progression PD variable presence of LBs Juvenile to 40 Recessive
PARK5[30] UCHL1 deubiquitinating enzyme Missense: Ile93Met[38] PD; late onset Parkinsonism Unknown; various abnormal protein aggregations 30–50 Dominant
PARK6[30] PINK1[39] mitochondrial Ser-Thr Kinase 40+ mutations[39]

-Mostly point mutations

-Deletions on C-terminus Kinase domain

Parkinsonism Unknown 30–50 Recessive
PARK7[30] DJ-1[40] oxidative stress response? -10 point mutations including C46A, C53A, C106 & WT regions[40]

- Large deletion in L166P

Early onset Parkinsonism Unknown 20–40 Recessive
PARK8[30] LRRK2 (dardarin) 12q12[41] unknown protein kinase G2019S most common[42] late-onset Parkinson's Disease[43] Diffuse LBs; LNs; ± tau inclusions; ± amyloid plaques 40–60 Dominant

Environmental risk factors

Exposure to pesticides, metals, solvents, and other toxicants has been studied as a factor in the development of Parkinson's disease.[44] While associations are consistent, no single environmental factor has definitive proven to cause Parkinson's in human.

Pesticides

See also: Paraquat § Parkinson's_disease, Rotenone § Parkinson's_disease, and Trichloroethylene

Evidence from epidemiological, animal, and in vitro studies suggests that exposure to pesticides increases the risk for Parkinson's disease.[44] 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.[44][45] Rural living, well-drinking, and farming were also associated with Parkinson's, which may be partly explained by pesticide exposure.[45] 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.[44]

Rotenone, a naturally derived insecticide, inhibits mitochondrial complex 1 and selectively damages dopaminergic neurons in the substantia nigra. Rodent studies show both temporary and chronic exposure can produce Parkinson-like pathology, including enteric nervous system changes.[46] Paraquat, a widely used herbicide, has been epidemiologically linked to higher Parkinson's risk, and rodent studies show it causes mitochondrial dysfunction, oxidative stress, and dopaminergic neuron loss.[47]

Carbon disulfide is a risk factor and has been identified in industrial worker case studies and has induced parkinsonism in mice.[48][49] It is mainly used in the manufacture of viscose rayon, cellophane film, rubber and carbon tetrachloride.[50]

Environmental–genetic factors

There is a relationship between CYP2D6 (G1934A) gene polymorphism and chronic pesticide exposure. 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.[34][51]

Metals

See also: Lead poisoning, Manganism, and Manganese

Lead, which was used in gasoline until 1995 and paint until 1978, is known to damage the nervous system in various ways.[44] A few studies have found that people with high levels of lead in their body had twice the risk of Parkinson's disease.[44] Epidemiological studies on lead, however, have found little evidence for a link with Parkinson's.[44] 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.[44]

Solvent

Air pollution

See also: Particulate matter and air pollution

Long-term exposure to air pollution may increase the risk of developing Parkinson's disease (PD). Elevated levels of particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO) have been found in association with presence of PD.[52] People living in areas with the highest levels of PM2.5 and NO2 were found to have significantly increased likelihood of developing PD compared to those in areas with lowest levels.[53] NO2, being the main pollutant created through road traffic, has previously been implicated in multiple neurodegenerative disorders, with new information connecting exposure directly to risk of PD.[52][54]

Medical risk factors

Brain injury

As of 2014, a direct link between head injuries and Parkinson's disease has not been found, although several biological processes observed after head injury overlap with pathways implicated in PD. Immediately after injury, the brain experiences chemical changes that create short- and long-term changes in physiology.[55]

Inflammation

Neuroinflammation is considered a contributing mechanism in Parkinson's disease.[56][57] Research has shown lasting activation of the brain’s immune cells, microglia, in regions affected by the disease, suggesting that inflammation may play a role in the gradual loss of dopamine-producing neurons.[58] While immune responses can be protective in the short term, chronic inflammation may damage neurons over time. Dopaminergic neurons appear to be particularly vulnerable under inflammatory conditions.[59] The normal production and breakdown of dopamine already place these cells under higher stress than other neurons. When inflammation is present, this may increase the neurons' susceptibility to damage and speed up degeneration.[60] Changes in dopamine signaling may then influence immune activity in the brain, creating a feedback loop to further worsen neuronal loss.

Lifestyle protective factors

Exercise and caffeine consumption are known to help decrease the risks of PD. Diet can also affect the level of risk: eating patterns rich in fruits, vegetables, whole grains, and fish, are associated with reduced risk of Parkinson's disease, while diets high in red meats and processed foods are associated with increased risk.[61]

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. There is evidence to suggest that exercise can reduce risk or delay development of PD (primary prevention). Higher levels of moderate to vigorous physical activity are associated with a lowered risk of PD. There are also indications that exercise may slow or halt PD progression (secondary prevention). For example, increased levels of physical activity have been associated with slower deterioration on measures of daily living activities. This was found regardless of people's initial physical activity levels. Finally, exercise may help to reduce some symptoms of PD (tertiary prevention).[62]

The types of exercise interventions that have been studied can be categorized as either aerobic or goal-based.[63] 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.[63] 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.[63]

Coffee and tea consumption

Epidemiological studies show that coffee consumption is associated with decreased mortality and lower rates of some neurological diseases, including Parkinson’s disease and type 2 diabetes. Coffee beans and roasted coffee can contain hundreds of individual compounds, including caffeine, chlorogenic acid (CGA), quercetin, trigonelline, caffeic acid, and phenylindane.[64][65][66] Underlying mechanisms are not yet understood.[67][65][68]

Diet

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.[69] 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.[61] Biological mechanisms related to possible cognitive protective effects are currently unknown.[70]

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