Causes of Parkinson's disease

Parkinson's disease (PD) is a degenerative disorder of the central nervous system. Most people with PD have idiopathic Parkinson's disease (having no specific known cause). A small proportion of cases, however, can be attributed to known genetic factors. Other factors such as environmental toxins, herbicides, pesticides, and fungicides, have been associated with the risk of developing PD, but no causal relationships have been proven.

Genetic factors

PDB rendering of Parkin (ligase)

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.[1] 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[2]

Mutations in specific genes have been conclusively shown to cause PD. A large number of these genes are linked to translation.[3][4] 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[2][5] 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[2][6][7] Furthermore, mutations in genes including those that code for SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD[8] 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.[9] The most extensively studied PD-related genes are SNCA and LRRK2.

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.[2][10] 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.[2] Level of alpha-synuclein expression correlates with disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication.[11] Missense mutations in SNCA are rare.[2] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[2] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[2]

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.[9] A significant number of autosomal-dominant Parkinson's disease cases are associated with mutations in the LRRK2 gene[12] 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.[2][9] There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.[2] Mutations in PINK1, PRKN, and DJ-1 may cause mitochondrial dysfunction, an element of both idiopathic and genetic PD.[11] Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia.[13] This could be relevant in PD cases associated with dementia.[13]

GBA gene

Mutations in GBA are known to cause Gaucher's disease.[2] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.[14] Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism.[15] 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.[15] 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.[15]

Genes underlying familial Parkinson's disease

Genes underlying familial PD
HGNC symbolGene LocusFunctionMutationsClinical PresentationsNeuropathologyAge at onsetInheritance
PARK1/PARK4[16]SNCA[17] (α-synuclein) 4q21[18]Unknown synaptic functionDuplicationsIdiopathic PD; some postural tremor; slow progressionLBsMid 20 - 30Dominant
SNCA 4q22[18]instructions for making a small protein called alpha-synuclei [19]

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

may regulate release of dopamine [19]

 TriplicationsPD (Parkinson's Disease); PD with dementia;diffuse LBs disease;aggressive course; can develop cognitive dysfunction, autonomic failure, and myoclonus[20] LBs and Lewy neurites; ± glial inclusions; hippocampal CA2 and CA3 loss Mid 20s - 30s
A53T, A30P E46K[21][22]Idiopathic PD; early on setparkinsonism and diffuse LBs LBs and LNs; ± tau inclusions; amyloid plaques30 - 60
PARK2[16]Parkin[23] E3 ubiquitin ligase[24]200+ possible mutations including:[24]

- Inactivating somatic mutations

- Frequent intragenic deletions

Early on set Parkinsonism; slow progression PDvariable presence of LBsJuvenile to 40Recessive
PARK5[16]UCHL1 deubiquitinating enzymeMissense: Ile93Met[25]PD; late on set parkinsonismUnknown; various abnormal protein aggregations30 - 50Dominant
PARK6[16]PINK1[26] mitochondrial Ser-Thr Kinase40+ mutations[26]

-Mostly point mutations

-Deletions on C-terminus Kinase domain

ParkinsonismUnknown30 - 50Recessive
PARK7[16]DJ-1[27] oxidative stress response?-10 point mutations including C46A, C53A, C106 & WT regions[27]

- Large deletion in L166P

Early onset ParkinsonismUnknown20 - 40Recessive
PARK8[16]LRRK2 (dardarin) 12q12[28]unknown protein kinaseG2019S most common[29]late-onset Parkinson's Disease[30]Diffuse LBs; LNs; ± tau inclusions; ± amyloid plaques40 - 60Dominant

Environmental factors

Exposure to pesticides, metals, solvents, and other toxicants has been studied as a factor in the development of Parkinson's disease.[31] 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.[32][33] 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.[31] 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.[31][34] Rural living, well-drinking, and farming were also associated with Parkinson's, which may be partly explained by pesticide exposure.[34] 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.[31]

Metals

Lead, which was used in gasoline until 1995 and paint until 1978, is known to damage the nervous system in various ways.[31] A few studies have found that people with high levels of lead in their body had twice the risk of Parkinson's disease.[31] Epidemiological studies on lead, however, have found little evidence for a link with Parkinson's.[31] 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.[31]

Head injuries

A study in 2018 notes that "Even a mild head injury, commonly called a concussion, makes veterans more likely to get Parkinson's disease later on in life" with this being "the same type of injury suffered by many Americans on the sports field or in a motor vehicle crash each year."[32] An earlier study, published in 2012, suggests that playing in the NFL triples the risk of Alzheimer's and Parkinson's disease.[35]

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 disease. The types of exercise interventions that have been studied can be categorized as either aerobic or goal-based.[36] 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.[36] 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.[36] While exercise has consistently been shown to be beneficial, the optimal interventional benefit is still being researched.[37]

Caffeine consumption

Studies have been done with groups of people where individuals (smokers and nonsmokers) with different rates of caffeine consumption were monitored for their susceptibility to PD. The results of these findings indicated that higher coffee/caffeine intake is associated with a significantly lower incidence of PD and that this effect appeared to be independent of smoking.[38]

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.[20][39]

References

  1. ↑ Samii, A; Nutt, JG; Ransom, BR (May 29, 2004). "Parkinson's disease". Lancet. 363 (9423): 1783–93. doi:10.1016/S0140-6736(04)16305-8. PMID 15172778. S2CID 35364322.
  2. 1 2 3 4 5 6 7 8 9 10 11 Lesage S, Brice A (April 2009). "Parkinson's disease: from monogenic forms to genetic susceptibility factors". Hum. Mol. Genet. 18 (R1): R48–59. doi:10.1093/hmg/ddp012. PMID 19297401.
  3. ↑ Correddu, D; Leung IKH (March 2019). "Targeting mRNA translation in Parkinson's disease". Drug Discovery Today. 24 (6): 1295–1303. doi:10.1016/j.drudis.2019.04.003. PMID 30974176. S2CID 109939167.
  4. ↑ Zhou, ZD; Selvaratnam T; Lee JCT; Chao YX; Tan EK (February 2019). "Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson's disease". Transl. Neurodegener. 8: 6. doi:10.1186/s40035-019-0145-0. PMC 6360798. PMID 30740222.
  5. ↑ Larsen, S. B.; Hanss, Z.; Krüger, R. (2018-01-25). "The genetic architecture of mitochondrial dysfunction in Parkinson's disease". Cell and Tissue Research. 373 (1): 21–37. doi:10.1007/s00441-017-2768-8. ISSN 1432-0878. PMC 6015629. PMID 29372317.
  6. ↑ Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86 (1): 109–27. doi:10.1093/bmb/ldn013. PMID 18398010.
  7. ↑ Kitada, T; Asakawa S; Hattori N; Matsumine H; Yamamura Y; Minoshima S; Yokochi M; Mizuno Y; Shimizu N. (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature. 392 (6676): 605–608. Bibcode:1998Natur.392..605K. doi:10.1038/33416. PMID 9560156. S2CID 4432261.
  8. ↑ Neumann, J; Bras J; Deas E; O'Sullivan SS; Parkkinen L; Lachmann RH; Li A; Holton J; Guerreiro R; Paudel R; Segarane B; Singleton A; Lees A; Hardy J; Houlden H; Revesz T; Wood NW. (March 2009). "Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease". Brain. 132 (7): 1783–94. doi:10.1093/brain/awp044. PMC 2702833. PMID 19286695.
  9. 1 2 3 Davie, CA (2008). "A review of Parkinson's disease". British Medical Bulletin. 86: 109–27. doi:10.1093/bmb/ldn013. PMID 18398010.
  10. ↑ Dhungel, Nripesh; Eleuteri, Simona; Li, Ling-bo; Kramer, Nicholas J.; Chartron, Justin W.; Spencer, Brian; Kosberg, Kori; Fields, Jerel Adam; Stafa, Klodjan (2015-01-07). "Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein". Neuron. 85 (1): 76–87. doi:10.1016/j.neuron.2014.11.027. ISSN 0896-6273. PMC 4289081. PMID 25533483.
  11. 1 2 Martin, I; Dawson, VL; Dawson, TM (Sep 2011). "Recent Advances in the Genetics of Parkinson's Disease". Annu. Rev. Genom. Hum. Genet. 12 (10): 301–25. doi:10.1146/annurev-genom-082410-101440. PMC 4120236. PMID 21639795.
  12. ↑ Funayama, M; Hasegawa K; Kowa H; Saito M; Tsuji S; Obata F. (March 2002). "A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1". Annals of Neurology. 51 (3): 296–301. doi:10.1002/ana.10113. PMID 11891824. S2CID 10360790.
  13. 1 2 Chen-Plotkin, AS; Martinez-Lage, M; Sleiman, PMA; Hu, W; et al. (Apr 2011). "Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration". Arch. Neurol. 68 (4): 488–97. doi:10.1001/archneurol.2011.53. PMC 3160280. PMID 21482928.
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  21. ↑ Lesage, S; Brice, A (Apr 15, 2009). "Parkinson's disease: from monogenic forms to genetic susceptibility factors". Human Molecular Genetics. 18 (R1): R48–59. doi:10.1093/hmg/ddp012. PMID 19297401.
  22. ↑ Teismann, P; Schulz, JB (Oct 2004). "Cellular pathology of Parkinson's disease: astrocytes, microglia and inflammation". Cell and Tissue Research. 318 (1): 149–61. doi:10.1007/s00441-004-0944-0. PMID 15338271. S2CID 19101756.
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  24. 1 2 Kim, SY; Seong, MW; Jeon, BS; Kim, SY; Ko, HS; Kim, JY; Park, SS (Jul 2012). "Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease". Clinical Genetics. 82 (1): 77–82. doi:10.1111/j.1399-0004.2011.01693.x. PMID 21534944. S2CID 36434515.
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  30. ↑ Haugarvoll, Kristoffer; Wszolek, Zbigniew K. (2009-12-01). "Clinical features of LRRK2 parkinsonism". Parkinsonism & Related Disorders. 15 Suppl 3: S205–208. doi:10.1016/S1353-8020(09)70815-6. ISSN 1873-5126. PMID 20082991.
  31. 1 2 3 4 5 6 7 8 Goldman SM (2014). "Environmental toxins and Parkinson's disease". Annu. Rev. Pharmacol. Toxicol. 54: 141–64. doi:10.1146/annurev-pharmtox-011613-135937. PMID 24050700.
  32. 1 2 "Even a mild head injury increases risk for Parkinson's disease, veterans study shows". ABC News. 2018-04-19.
  33. ↑ https://www.usnews.com/news/articles/2012/09/05/playing-in-nfl-triples-risk-of-alzheimers-parkinsons-diseases/
  34. 1 2 Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, Schrag A (2012). "Meta-analysis of early nonmotor features and risk factors for Parkinson disease". Ann. Neurol. 72 (6): 893–901. doi:10.1002/ana.23687. PMC 3556649. PMID 23071076.
  35. ↑ https://www.usnews.com/news/articles/2012/09/05/playing-in-nfl-triples-risk-of-alzheimers-parkinsons-diseases
  36. 1 2 3 Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW (2013). "Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease". The Lancet Neurology. 12 (7): 716–726. doi:10.1016/S1474-4422(13)70123-6. PMC 3690528. PMID 23769598.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  37. ↑ Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL (2008). "The effectiveness of exercise interventions for people with Parkinson's disease: A systematic review and meta-analysis". Mov Disord. 23 (5): 631–640. doi:10.1002/mds.21922. hdl:10871/17451. PMID 18181210. S2CID 3808899.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ↑ Tsuboi Y (2012). "Environmental-genetic interactions in the pathogenesis of Parkinson's disease". Exp Neurobiol. 21 (3): 123–8. doi:10.5607/en.2012.21.3.123. PMC 3454809. PMID 23055790.
  39. ↑ Elbaz, Alexis; Levecque, Clotilde; Clavel, Jacqueline; Vidal, Jean-Sébastien; Richard, Florence; Amouyel, Philippe; Alpérovitch, Annick; Chartier-Harlin, Marie-Christine; Tzourio, Christophe (2004-03-01). "CYP2D6 polymorphism, pesticide exposure, and Parkinson's disease". Annals of Neurology. 55 (3): 430–434. doi:10.1002/ana.20051. ISSN 1531-8249. PMID 14991823. S2CID 19772933.
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