Parkinson's disease causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Causes

although most of the cases of Parkinson disease are sporadic and idiopathic, there are some underlying cause for this disease including:

Genetics

There are some evidence showing that there is an association between PD and genetic. This role is higher when Parkinson disease occurs in the individual younger than 50 years old.[1] these studies also demonstrate that if a person has a first degree with PD, the risk of developing PD is 2 to 3 times higher than normal population. Conversely, in 25 to 50 % of PD patients we can find at least one first degree having PD.[2]

Some of specific genes involving in PD are:

Protein misfolding

One of the main underlying cause of PD is mutation in the gene of alpha-synuclein protein which is abundant in the CNS. Its function is thought to be involved in synaptic function and plasticity.[9][10] This mutations lead to unfold alpha-synuclein and aggregation of insoluble protein and neuronal damage. Lewy bodies which are characteristic of PD are mostly build from alpha-synuclein protein.[11]

Defective proteolysis

There are three pathways which control the protein homeostasis in cells: Molecular chaperons, the ubiquitin-proteasome system and autophagy-lysosomal pathway. Alpha synuclein processing is done by all of this three mechanisms and defect in any of them can cause aggregation of this protein and neuronal death.[12][13][14]

Mitochondrial dysfunction

The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an analog of mepridine is found to be associated with PD. The oxidation of this drug produces 1-methyl-4-phenylpyridium which inhibits complex one of mitochondria and result in cell damage. Studies showed that the activity of this complex is decreased in PD patients.[20][21][22]

Oxidative stress

Reactive oxygen species including hydrogen peroxide, superoxide anions and hydroxyradicals are toxic to neurons and cause neuronal damage. They interact with membrane lipids and cause lipid peroxidation which can be seen in substantia nigra of PD patients.[23][24] They can also cause protein misfolding by attacking disulfide isomerase through nitric oxide. Disulfide isomerase is a chaperone preventing the aggregation of proteins.[25]

Iron metabolism

Studies showed that impaired iron metabolism leads to increase amount of iron in substantia nigra of PD patients. One of the underlying etiology of iron accommodation in neuronal cells is the absence of tau protein.[26][27][28]

Immunologic and inflammatory mechanisms

There are some studies supporting the idea of immunologic mechanisms causing PD.[29] In PD patients there is elevated amounts of cyclooxygenase-2 which is the rate limiting enzyme in prostaglandin E2 synthesis.[30] Neuronal cell death can also occur due to infiltration of CD4+ T cells.[31]

References

  1. ↑ Singleton AB, Farrer MJ, Bonifati V (January 2013). "The genetics of Parkinson's disease: progress and therapeutic implications". Mov. Disord. 28 (1): 14–23. doi:10.1002/mds.25249. PMC 3578399. PMID 23389780.
  2. ↑ Marder K, Tang MX, Mejia H, Alfaro B, Côté L, Louis E, Groves J, Mayeux R (July 1996). "Risk of Parkinson's disease among first-degree relatives: A community-based study". Neurology. 47 (1): 155–60. PMID 8710070.
  3. ↑ Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG (October 2009). "Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease". N. Engl. J. Med. 361 (17): 1651–61. doi:10.1056/NEJMoa0901281. PMC 2856322. PMID 19846850.
  4. ↑ Klein C, Schlossmacher MG (November 2007). "Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder". Neurology. 69 (22): 2093–104. doi:10.1212/01.wnl.0000271880.27321.a7. PMID 17761553.
  5. ↑ 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". Ann. Neurol. 51 (3): 296–301. PMID 11891824.
  6. ↑ Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A (May 2000). "Association between early-onset Parkinson's disease and mutations in the parkin gene". N. Engl. J. Med. 342 (21): 1560–7. doi:10.1056/NEJM200005253422103. PMID 10824074.
  7. ↑ Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (May 2004). "Hereditary early-onset Parkinson's disease caused by mutations in PINK1". Science. 304 (5674): 1158–60. doi:10.1126/science.1096284. PMID 15087508.
  8. ↑ 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 (January 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.
  9. ↑ Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K (September 2003). "The role of alpha-synuclein in Parkinson's disease: insights from animal models". Nat. Rev. Neurosci. 4 (9): 727–38. doi:10.1038/nrn1199. PMID 12951565.
  10. ↑ Calo L, Wegrzynowicz M, Santivañez-Perez J, Grazia Spillantini M (February 2016). "Synaptic failure and α-synuclein". Mov. Disord. 31 (2): 169–77. doi:10.1002/mds.26479. PMID 26790375.
  11. ↑ Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (August 1997). "Alpha-synuclein in Lewy bodies". Nature. 388 (6645): 839–40. doi:10.1038/42166. PMID 9278044.
  12. ↑ Lim KL, Zhang CW (2013). "Molecular events underlying Parkinson's disease - an interwoven tapestry". Front Neurol. 4: 33. doi:10.3389/fneur.2013.00033. PMC 3619247. PMID 23580245.
  13. ↑ Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E (June 2013). "Lysosomal impairment in Parkinson's disease". Mov. Disord. 28 (6): 725–32. doi:10.1002/mds.25462. PMC 5131721. PMID 23580333.
  14. ↑ Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Łos MJ (January 2014). "Autophagy and apoptosis dysfunction in neurodegenerative disorders". Prog. Neurobiol. 112: 24–49. doi:10.1016/j.pneurobio.2013.10.004. PMID 24211851.
  15. ↑ Tolosa E, Wenning G, Poewe W (January 2006). "The diagnosis of Parkinson's disease". Lancet Neurol. 5 (1): 75–86. doi:10.1016/S1474-4422(05)70285-4. PMID 16361025.
  16. ↑ Mena MA, de Yébenes JG (November 2006). "Drug-induced parkinsonism". Expert Opin Drug Saf. 5 (6): 759–71. doi:10.1517/14740338.5.6.759. PMID 17044803.
  17. ↑ Savica R, Grossardt BR, Bower JH, Ahlskog JE, Mielke MM, Rocca WA (February 2017). "Incidence and time trends of drug-induced parkinsonism: A 30-year population-based study". Mov. Disord. 32 (2): 227–234. doi:10.1002/mds.26839. PMC 5318251. PMID 27779780.
  18. ↑ Hardie RJ, Lees AJ (June 1988). "Neuroleptic-induced Parkinson's syndrome: clinical features and results of treatment with levodopa". J. Neurol. Neurosurg. Psychiatry. 51 (6): 850–4. PMC 1033159. PMID 2900293.
  19. ↑ Jankovic J, Casabona J (December 1987). "Coexistent tardive dyskinesia and parkinsonism". Clin Neuropharmacol. 10 (6): 511–21. PMID 2892586.
  20. ↑ Przedborski S, Tieu K, Perier C, Vila M (August 2004). "MPTP as a mitochondrial neurotoxic model of Parkinson's disease". J. Bioenerg. Biomembr. 36 (4): 375–9. doi:10.1023/B:JOBB.0000041771.66775.d5. PMID 15377875.
  21. ↑ Selvaraj S, Sun Y, Watt JA, Wang S, Lei S, Birnbaumer L, Singh BB (April 2012). "Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling". J. Clin. Invest. 122 (4): 1354–67. doi:10.1172/JCI61332. PMC 3314472. PMID 22446186.
  22. ↑ Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (June 1989). "Mitochondrial complex I deficiency in Parkinson's disease". Lancet. 1 (8649): 1269. PMID 2566813.
  23. ↑ Greenamyre JT, Hastings TG (May 2004). "Biomedicine. Parkinson's--divergent causes, convergent mechanisms". Science. 304 (5674): 1120–2. doi:10.1126/science.1098966. PMID 15155938.
  24. ↑ Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT (November 2003). "Mechanism of toxicity in rotenone models of Parkinson's disease". J. Neurosci. 23 (34): 10756–64. PMID 14645467.
  25. ↑ Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (May 2006). "S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration". Nature. 441 (7092): 513–7. doi:10.1038/nature04782. PMID 16724068.
  26. ↑ Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (May 2007). "Individual dopaminergic neurons show raised iron levels in Parkinson disease". Neurology. 68 (21): 1820–5. doi:10.1212/01.wnl.0000262033.01945.9a. PMID 17515544.
  27. ↑ Dusek P, Jankovic J, Le W (April 2012). "Iron dysregulation in movement disorders". Neurobiol. Dis. 46 (1): 1–18. doi:10.1016/j.nbd.2011.12.054. PMID 22266337.
  28. ↑ Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI (January 2012). "Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export". Nat. Med. 18 (2): 291–5. doi:10.1038/nm.2613. PMID 22286308.
  29. ↑ Hirsch EC, Hunot S (April 2009). "Neuroinflammation in Parkinson's disease: a target for neuroprotection?". Lancet Neurol. 8 (4): 382–97. doi:10.1016/S1474-4422(09)70062-6. PMID 19296921.
  30. ↑ Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S (April 2003). "Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5473–8. doi:10.1073/pnas.0837397100. PMC 154369. PMID 12702778.
  31. ↑ Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (January 2009). "Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease". J. Clin. Invest. 119 (1): 182–92. doi:10.1172/JCI36470. PMC 2613467. PMID 19104149.

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