Parkinson's disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Overview

The underlying pathophysiology of Parkinson disease is dopamine depletion. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia. pathologic hallmark of PD is lewy bodies which are round cytoplasmic eosinophilic inclusions. This disease can have so many triggers ( Protein misfolding, Defective proteolysis, Mitochondrial dysfunction, Oxidative stress, Iron metabolism and Immunologic and inflammatory mechanisms) but the main etiology of neuronal degeneration is either apoptosis or necrosis.

Pathophysiology

Physiology

Phatogenesis

Protein misfolding

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.[18][19][20]

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.[21][22][23]

Oxidative stress

Iron metabolism

Immunologic and inflammatory mechanisms

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.[33]
  • 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.[34]

Some of specific genes involving in PD are:

Microscopic Pathology

https://librepathology.org/wiki/File:Histological_sample_of_Substantia_nigra_in_Parkinson%27s_disease.jpg
https://librepathology.org/wiki/File:Lewy_bodies_(alpha_synuclein_inclusions).jpg
https://librepathology.org/wiki/File:Lewy_Body_alphaSynuclein.jpg
https://librepathology.org/wiki/File:Journal.pone.0008247.g001.png

References

  1. Gerfen CR (October 2000). "Molecular effects of dopamine on striatal-projection pathways". Trends Neurosci. 23 (10 Suppl): S64–70. PMID 11052222.
  2. Bamford NS, Robinson S, Palmiter RD, Joyce JA, Moore C, Meshul CK (October 2004). "Dopamine modulates release from corticostriatal terminals". J. Neurosci. 24 (43): 9541–52. doi:10.1523/JNEUROSCI.2891-04.2004. PMID 15509741.
  3. Gatev P, Darbin O, Wichmann T (October 2006). "Oscillations in the basal ganglia under normal conditions and in movement disorders". Mov. Disord. 21 (10): 1566–77. doi:10.1002/mds.21033. PMID 16830313.
  4. Calabresi P, Centonze D, Bernardi G (October 2000). "Electrophysiology of dopamine in normal and denervated striatal neurons". Trends Neurosci. 23 (10 Suppl): S57–63. PMID 11052221.
  5. Moore H, Grace AA (December 2002). "A role for electrotonic coupling in the striatum in the expression of dopamine receptor-mediated stereotypies". Neuropsychopharmacology. 27 (6): 980–92. doi:10.1016/S0893-133X(02)00383-4. PMID 12464455.
  6. Adams JR, van Netten H, Schulzer M, Mak E, Mckenzie J, Strongosky A, Sossi V, Ruth TJ, Lee CS, Farrer M, Gasser T, Uitti RJ, Calne DB, Wszolek ZK, Stoessl AJ (December 2005). "PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation". Brain. 128 (Pt 12): 2777–85. doi:10.1093/brain/awh607. PMID 16081470.
  7. Pakkenberg B, Møller A, Gundersen HJ, Mouritzen Dam A, Pakkenberg H (January 1991). "The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method". J. Neurol. Neurosurg. Psychiatry. 54 (1): 30–3. PMC 1014294. PMID 2010756.
  8. Porritt M, Stanic D, Finkelstein D, Batchelor P, Lockhart S, Hughes A, Kalnins R, Howells D (July 2005). "Dopaminergic innervation of the human striatum in Parkinson's disease". Mov. Disord. 20 (7): 810–8. doi:10.1002/mds.20399. PMID 15726582.
  9. Fearnley JM, Lees AJ (October 1991). "Ageing and Parkinson's disease: substantia nigra regional selectivity". Brain. 114 ( Pt 5): 2283–301. PMID 1933245.
  10. Henderson JM, Carpenter K, Cartwright H, Halliday GM (March 2000). "Degeneration of the centré median-parafascicular complex in Parkinson's disease". Ann. Neurol. 47 (3): 345–52. PMID 10716254.
  11. Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA (July 2003). "Parkinson's disease is associated with hippocampal atrophy". Mov. Disord. 18 (7): 784–90. doi:10.1002/mds.10444. PMID 12815657.
  12. Savitt JM, Dawson VL, Dawson TM (July 2006). "Diagnosis and treatment of Parkinson disease: molecules to medicine". J. Clin. Invest. 116 (7): 1744–54. doi:10.1172/JCI29178. PMC 1483178. PMID 16823471.
  13. Lang AE (March 2007). "The progression of Parkinson disease: a hypothesis". Neurology. 68 (12): 948–52. doi:10.1212/01.wnl.0000257110.91041.5d. PMID 17372132.
  14. Atkin G, Paulson H (2014). "Ubiquitin pathways in neurodegenerative disease". Front Mol Neurosci. 7: 63. doi:10.3389/fnmol.2014.00063. PMC 4085722. PMID 25071440.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. 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.
  41. Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, Harigaya Y, Sasaki A, Takahashi R, Abe K (March 2004). "Pael-R is accumulated in Lewy bodies of Parkinson's disease". Ann. Neurol. 55 (3): 439–42. doi:10.1002/ana.20064. PMID 14991825.
  42. Pan T, Kondo S, Le W, Jankovic J (August 2008). "The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease". Brain. 131 (Pt 8): 1969–78. doi:10.1093/brain/awm318. PMID 18187492.
  43. Jellinger KA (2000). "Cell death mechanisms in Parkinson's disease". J Neural Transm (Vienna). 107 (1): 1–29. doi:10.1007/s007020050001. PMID 10809400.
  44. Tatton WG, Chalmers-Redman R, Brown D, Tatton N (2003). "Apoptosis in Parkinson's disease: signals for neuronal degradation". Ann. Neurol. 53 Suppl 3: S61–70, discussion S70–2. doi:10.1002/ana.10489. PMID 12666099.

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