Causes of Parkinson's disease

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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)(LRRK2and Htra2 respectively [2] Genes such as PARK2, PARK, 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 [4][5][6] Furthermore, mutations in genes including those that code for SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD [7] 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.[8] 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] SNCA is expressed throughout the mammalian brain and enriched in presynaptic nerve terminals. 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.[9]

LARRK2 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.[8] 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][8] 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.[9] Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia.[10] This could be relevant in PD cases associated with dementia.[10]

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.[11] Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism.[12] 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.[12]

Genes Underlying Familial Parkinson's Disease

Genes underlying familial PD
Locus Gene Function Mutations Clinical Presentations Neuropathology Age at onset Inheritance
PARK1/PARK4[13] SNCA[14] (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[15][16] Idiopathic PD; early on setparkinsonism and diffuse LBs LBs and LNs; ± tau inclusions; amyloid plaques 30 - 60
PARK2[13] Parkin[17] E3 ubiquitin ligase[18] 200+ possible mutations including:[18]

- Inactivating somatic mutations

- Frequent intragenic deletions

 Early on set Parkinsonism; slow progression PD variable presence of LBs Juvenile to 40 Recessive
PARK5[13] UCHL1 deubiquitinating enzyme Missense: Ile93Met [19] PD; late on set parkinsonism Unknown; various abnormal protein aggregations 30 - 50 Dominant
PARK6[13] PINK1[20] mitochondrial Ser-Thr Kinase 40+ mutations[20]

-Mostly point mutations

-Deletions on C-terminus Kinase domain

 Parkinsonism Unknown 30 - 50 Recessive
PARK7[13] DJ-1[21] oxidative stress response? -10 point mutations including C46A, C53A, C106 & WT regions[21]

- Large deletion in L166P

 Early onset Parkinsonism Unknown 20 - 40 Recessive
PARK8[13] LRRK2 (dardarin) unknown protein kinase G2019S most common [22] PD Diffuse LBs; LNs; ± tau inclusions; ± amyloid plaques 40 - 60 Dominant

Overview

PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In addition, common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated.

Environmental Factors

Several environmental factors including toxins, pesticides,and metals have been implicated in the development of Parkinson's Disease, although a definitive causal relationship between these toxins and PD has not been determined. Current research has proposed multiple mechanisms through which these toxins may lead to the development of Parkinson's disease.

β-Methylamino-L-Alanine

beta-Methylamino-L-alanine or BMAA, a non-protein amino acid produced by Cyanobacteria commonly found in contaminated seafood, drinking water and recreational waters might be a major factor in PD.[23] Concrete evidence about the role of BMAA in neuronal dysfunction exhibited in PD has not been found, although current research suggests multiple mechanisms. Studies show that BMAA can be misincorporated into human proteins in place of L-Serine, leading to protein misfolding and abnormal protein aggregation.[24] In this way, BMAA incorporation into human proteins might lead to the formation of Lewy bodies, which develop within nerve cells of the substantia nigra and other brain regions in PD.[24] Increased amounts of L-Serine has shown to inhibit BMAA incorporation into human proteins.[24] Studies have also found that BMAA is an excitotoxin for glutamate receptors, including NMDA, AMPA and kainate receptors.[25] Overstimulation of glutamate receptors leads to increased Reactive oxygen species, resulting in motor neuron injury associated with neurodegenerative diseases such as PD.[25] Another study found that BMAA decreases levels of reduced glutathione, a major antioxidant within the body, which also contributes to neuronal injury.[26]

Organochlorine Pesticides

Organochlorine pesticides might play a role in the development of PD. One study compared organochlorine compound concentrations in the substantia nigra of PD patients, Cortical Lewy Body Dementia patients, Alzheimer's Disease patients and healthy controls.[27] Concentrations of hexachlorocyclohexane (gammaHCH, lindane) appeared to be higher in the brains of PD patients, compared to Alzheimer's Disease patients and controls, whereas levels of Dieldrin were higher in the PD brain as compared to the AD patients' brains and controls. Concentrations of 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) and polychlorinated biphenyls appeared to be higher in PD brains only when compared to Cortical Lewy Body Dementia.[27] Another study also found increased concentration of Dieldrin in 6 of 20 PD brains compared to none in controls[28] Organochlorine pesticides might act as mitochondrial-poisons, leading to increased oxidative stress within neurons and resulting in dopaminergic neuronal body damage associated with Parkinson's disease.[27]

References

  1. ↑ Samii, A; Nutt, JG; Ransom, BR (2004 May 29). "Parkinson's disease.". Lancet 363 (9423): 1783–93. doi:10.1016/S0140-6736(04)16305-8. PMID 15172778. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 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. ↑ 3.0 3.1 Funayama, M; Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. (2002 March). "A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1.". Annals of Neurology 51 (3): 296–301. PMID 19286695. 
  4. ↑ 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. 
  5. ↑ Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86 (1): 109–27. doi:10.1093/bmb/ldn013. PMID 18398010. 
  6. ↑ Kitada, T; Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. (1998 April). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.". Nature 392 (6676): 605–608. PMID 9560156. 
  7. ↑ 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. (2009 March). "Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease.". Brain 132 (7): 1783–94. PMID 19286695. 
  8. ↑ 8.0 8.1 8.2 Davie, CA (2008). "A review of Parkinson's disease.". British Medical Bulletin 86: 109–27. doi:10.1093/bmb/ldn013. PMID 18398010. 
  9. ↑ 9.0 9.1 Martin, I; Dawson, VL; Dawson, TM (2011 Sept). "Recent Advances in the Genetics of Parkinson’s Disease.". Annu. Rev. Genomics Hum. Genet. 12: 301–25. doi:10.1146/annurev-genom-082410-101440. PMID 2639795. 
  10. ↑ 10.0 10.1 Chen-Plotkin, AS; Martinez-Lage, M; Sleiman, PMA; Hu, W; et al. (2011 Apr). "Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration.". Arch Neurol. 68 (4): 488–97. doi:10.1001/archneurol.2011.53. PMID 21482928. 
  11. ↑ 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. PMID 21292315. 
  12. ↑ 12.0 12.1 Sidransy, E; Lopez, G (2012 Nov). "The link between the GBA gene and parkinsonism". Lancet Neurol. 11: 986–98. doi:10.1016/S1474-4422. PMID 23079555. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 Wood-Kaczmar, A; Gandhi, S; Wood, NW (2006 Nov). "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. 
  14. ↑ 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. 
  15. ↑ Lesage, S; Brice, A (2009 Apr 15). "Parkinson's disease: from monogenic forms to genetic susceptibility factors.". Human Molecular Genetics 18 (R1): R48–59. doi:10.1093/hmg/ddp012. PMID 19297401. 
  16. ↑ Teismann, P; Schulz, JB (2004 Oct). "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. 
  17. ↑ Thompson, SJ; Loftus, LT; Ashley, MD; Meller, R (2008 Feb). "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. 
  18. ↑ 18.0 18.1 Kim, SY; Seong, MW; Jeon, BS; Kim, SY; Ko, HS; Kim, JY; Park, SS (2012 Jul). "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. 
  19. ↑ 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 (1998 Oct 1). "The ubiquitin pathway in Parkinson’s disease.". Nature 395: 451–2. doi:10.1038/26652. PMID 9774100. 
  20. ↑ 20.0 20.1 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 (2004 Sep). "Novel PINK1 mutations in early-onset parkinsonism.". Annals of neurology 56 (3): 424–7. doi:10.1002/ana.20251. PMID 15349870. 
  21. ↑ 21.0 21.1 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 (2003 Jan 10). "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. 
  22. ↑ Hernandez, D; Paisan Ruiz, C; Crawley, A; Malkani, R; Werner, J; Gwinn-Hardy, K; Dickson, D; Wavrant Devrieze, F; Hardy, J; Singleton, A (2005 Dec). "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. 
  23. ↑ Brand, LE; Pablo, J; Compton, A; Hammerschlag, N; Mash, DC (2010 Sept). "Cyanobacterial Blooms and the Occurrence of the neurotoxin beta-N-methylamino-L-alanine (BMAA) in South Florida Aquatic Food Webs". Harmful Algae 9 (6): 986–98. PMID 21057660. 
  24. ↑ 24.0 24.1 24.2 Dunlop, RA; Cox, PA; Banack,SA; Rodgers, KJR (2013 Sept). "The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation". PLoS One 8 (9). doi:10.1371. PMID 24086518. 
  25. ↑ 25.0 25.1 Rao, SD; Banack, SA; Cox, PA; Weissa, JH (2006– Sept). "BMAA selectively injures motor neurons via AMPA/kainate receptor activation.". Experimental Neurology 201 (1): 986–98. 
  26. ↑ Chi, L; Ke, Y; Luo, C; Gozal, D; Liu, R (2007 August). "Depletion of Reduced Glutathione Enhances Motor Neuron Degeneration in vitro and in vivo.". Neuroscience 144 (3): 991–1003. PMID 16764863. 
  27. ↑ 27.0 27.1 27.2 Corrigan, FM; Wienburg CL, Shore RF, Daniel SE, Mann D. (2005). "Organochlorine insecticides in substantia nigra in Parkinson's disease.". J Toxicol Environ Health A 59 (4): 229–34. PMID 10706031. 
  28. ↑ Fleming, L; Mann JB, Bean J, Briggle T, Sanchez-Ramos JR. (2000 Feb). "Organochlorine insecticides in substantia nigra in Parkinson's disease.". J Toxicol Environ Health A 59 (4): 229–34. PMID 10706031. 
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