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, PD 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][3]

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

SNCA gene

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.[2] 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] 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] Level of alpha-synuclein expression correlates with disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication.[8]

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.[7] A significant number of autosomal-dominant Parkinson's disease cases are associated with mutations in the LRRK2 gene[3] 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][7] 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.[8] Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia.[9] This could be relevant in PD cases associated with dementia.[9]

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.[10] Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism.[11] 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.[11]

Genes underlying familial Parkinson's disease

Genes underlying familial PD
Locus Gene Function Mutations Clinical Presentations Neuropathology Age at onset Inheritance
PARK1/PARK4[12] SNCA[13] (α-synuclein) Unknown synaptic function Duplications Idiopathic PD; some postural tremor; slow progression LBs Mid 20 - 30 Dominant
Triplications PD (Parkinson's Disease); PD with dementia;diffuse LBs disease;aggressive course LBs and Lewy neurites; ± glial inclusions; hippocampal CA2 and CA3 loss Mid 20's - 30's
A53T, A30P E46K[14][15] Idiopathic PD; early on setparkinsonism and diffuse LBs LBs and LNs; ± tau inclusions; amyloid plaques 30 - 60
PARK2[12] Parkin[16] E3 ubiquitin ligase[17] 200+ possible mutations including:[17]

- Inactivating somatic mutations

- Frequent intragenic deletions

 Early on set Parkinsonism; slow progression PD variable presence of LBs Juvenile to 40 Recessive
PARK5[12] UCHL1 deubiquitinating enzyme Missense: Ile93Met[18] PD; late on set parkinsonism Unknown; various abnormal protein aggregations 30 - 50 Dominant
PARK6[12] PINK1[19] mitochondrial Ser-Thr Kinase 40+ mutations[19]

-Mostly point mutations

-Deletions on C-terminus Kinase domain

 Parkinsonism Unknown 30 - 50 Recessive
PARK7[12] DJ-1[20] oxidative stress response? -10 point mutations including C46A, C53A, C106 & WT regions[20]

- Large deletion in L166P

 Early onset Parkinsonism Unknown 20 - 40 Recessive
PARK8[12] LRRK2 (dardarin) unknown protein kinase G2019S most common[21] PD 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.[22] No definitive causal relationship has yet been established.

Pesticides

Evidence from epidemiological, animal, and in vitro studies suggests that exposure to pesticides increases the risk for Parkinson's disease.[22] 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.[22][23] Rural living, well-drinking, and farming were also associated with Parkinson's, which may be partly explained by pesticide exposure.[23] 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.[22]

Metals

Lead, which was used in gasoline until 1995 and paint until 1978, is known to damage the nervous system in various ways.[22] A few studies have found that people with high levels of lead in their body had twice the risk of Parkinson's disease.[22] Epidemiological studies on lead, however, have found little evidence for a link with Parkinson's.[22] 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.[22]

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.
  2. 1 2 3 4 5 6 7 8 9 10 11 Lesage S, Brice A; Brice (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. 1 2 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.
  4. ↑ Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86 (1): 109–27. doi:10.1093/bmb/ldn013. PMID 18398010.
  5. ↑ 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.
  6. ↑ 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.
  7. 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.
  8. 1 2 Martin, I; Dawson, VL; Dawson, TM (Sep 2011). "Recent Advances in the Genetics of Parkinson’s Disease.". Annu. Rev. Genomics Hum. Genet. 12 (10): 301–25. doi:10.1146/annurev-genom-082410-101440. PMID 2639795.
  9. 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. PMID 21482928.
  10. ↑ IPDGC; Nalls, MA; Plagnol, V; Hernandez, DG; Sharma, M; Sheerin, UM; Saad, M; Simón-Sánchez, J; et al. (2011). "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies". Lancet 377 (9766): 641–649. doi:10.1016/S0140-6736(10)62345-8. PMC 3696507. PMID 21292315.
  11. 1 2 Sidransy, E; Lopez, G (Nov 2012). "The link between the GBA gene and parkinsonism". Lancet Neurol. 11 (11): 986–98. doi:10.1016/S1474-4422(12)70190-4. PMC 4141416. PMID 23079555.
  12. 1 2 3 4 5 6 Wood-Kaczmar, A; Gandhi, S; Wood, NW (Nov 2006). "Understanding the molecular causes of Parkinson's disease.". Trends in molecular medicine 12 (11): 521–8. doi:10.1016/j.molmed.2006.09.007. PMID 17027339.
  13. ↑ Cookson, MR (2005). "The biochemistry of Parkinson's disease.". Annual Review of Biochemistry 74: 29–52. doi:10.1146/annurev.biochem.74.082803.133400. PMID 15952880.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Thompson, SJ; Loftus, LT; Ashley, MD; Meller, R (Feb 2008). "Ubiquitin-proteasome system as a modulator of cell fate.". Current Opinion in Pharmacology 8 (1): 90–5. doi:10.1016/j.coph.2007.09.010. PMC 2265078. PMID 17981502.
  17. 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.
  18. ↑ Leroy, E; Boyer, R; Auburger, G; Leube, B; Ulm, G; Mezey, E; Harta, G; Brownstein, MJ; Jonnalagada, S; Chernova, T; Dehejia, A; Lavedan, C; Gasser, T; Steinbach, PJ; Wilkinson, KD; Polymeropolous MH; Auburger, Georg; Leube, Barbara; Ulm, Gudrun; Mezey, Eva; Harta, Gyongyi; Brownstein, Michael J.; Jonnalagada, Sobhanadditya; Chernova, Tanya; Dehejia, Anindya; Lavedan, Christian; Gasser, Thomas; Steinbach, Peter J.; Wilkinson, Keith D.; Polymeropoulos, Mihael H. (Oct 1, 1998). "The ubiquitin pathway in Parkinson's disease". Nature 395 (6701): 451–2. Bibcode:1998Natur.395..451L. doi:10.1038/26652. PMID 9774100.
  19. 1 2 Hatano, Y; Li, Y; Sato, K; Asakawa, S; Yamamura, Y; Tomiyama, H; Yoshino, H; Asahina, M; Kobayashi, S; Hassin-Baer, S; Lu, CS; Ng, AR; Rosales, RL; Shimizu, N; Toda, T; Mizuno, Y; Hattori, N (Sep 2004). "Novel PINK1 mutations in early-onset parkinsonism". Annals of Neurology 56 (3): 424–7. doi:10.1002/ana.20251. PMID 15349870.
  20. 1 2 Bonifati, V; Rizzu, P; van Baren, MJ; Schaap, O; Breedveld, GJ; Krieger, E; Dekker, MC; Squitieri, F; Ibanez, P; Joosse, M; van Dongen, JW; Vanacore, N; van Swieten, JC; Brice, A; Meco, G; van Duijn, CM; Oostra, BA; Heutink, P (Jan 10, 2003). "Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism". Science 299 (5604): 256–9. doi:10.1126/science.1077209. PMID 12446870.
  21. ↑ Hernandez, D; Paisan Ruiz, C; Crawley, A; Malkani, R; Werner, J; Gwinn-Hardy, K; Dickson, D; Wavrant Devrieze, F; Hardy, J; Singleton, A (Dec 2005). "The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases". Neuroscience Letters 389 (3): 137–9. doi:10.1016/j.neulet.2005.07.044. PMID 16102903.
  22. 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.
  23. 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.
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