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


Most people with Parkinson's disease are described as having [[idiopathic]] Parkinson's disease (having no specific cause). There are far less common causes of Parkinson's disease including
====Genetics====
* Genetic
There are some evidence showing that there is an association between [[Parkinson's disease|PD]] and [[genetic]]. This role is higher when Parkinson disease occurs in the individual younger than 50 years old.<ref name="pmid23389780">{{cite journal |vauthors=Singleton AB, Farrer MJ, Bonifati V |title=The genetics of Parkinson's disease: progress and therapeutic implications |journal=Mov. Disord. |volume=28 |issue=1 |pages=14–23 |date=January 2013 |pmid=23389780 |pmc=3578399 |doi=10.1002/mds.25249 |url=}}</ref> these studies also demonstrate that if a person has a first degree with [[Parkinson's disease|PD]], the risk of developing [[Parkinson's disease|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 [[Parkinson's disease|PD]].<ref name="pmid8710070">{{cite journal |vauthors=Marder K, Tang MX, Mejia H, Alfaro B, Côté L, Louis E, Groves J, Mayeux R |title=Risk of Parkinson's disease among first-degree relatives: A community-based study |journal=Neurology |volume=47 |issue=1 |pages=155–60 |date=July 1996 |pmid=8710070 |doi= |url=}}</ref>
* Toxins - MPTP, paraquat, rotenone
* Head trauma
* Drug-induced - Antipsychotics, Dopamine agonists


Some of specific genes involving in [[Parkinson's disease|PD]] are:
*[[Glucocerebrosidase|Glucocerebrosidase gene]] <ref name="pmid19846850">{{cite journal |vauthors=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 |title=Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease |journal=N. Engl. J. Med. |volume=361 |issue=17 |pages=1651–61 |date=October 2009 |pmid=19846850 |pmc=2856322 |doi=10.1056/NEJMoa0901281 |url=}}</ref>
*[[SNCA]]-associated PD <ref name="pmid17761553">{{cite journal |vauthors=Klein C, Schlossmacher MG |title=Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder |journal=Neurology |volume=69 |issue=22 |pages=2093–104 |date=November 2007 |pmid=17761553 |doi=10.1212/01.wnl.0000271880.27321.a7 |url=}}</ref>
*[[LRRK2]]-associated PD <ref name="pmid11891824">{{cite journal |vauthors=Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F |title=A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1 |journal=Ann. Neurol. |volume=51 |issue=3 |pages=296–301 |date=March 2002 |pmid=11891824 |doi= |url=}}</ref>
*[[Parkin]]-associated PD <ref name="pmid10824074">{{cite journal |vauthors=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 |title=Association between early-onset Parkinson's disease and mutations in the parkin gene |journal=N. Engl. J. Med. |volume=342 |issue=21 |pages=1560–7 |date=May 2000 |pmid=10824074 |doi=10.1056/NEJM200005253422103 |url=}}</ref>
*[[PINK1]]-associated PD <ref name="pmid15087508">{{cite journal |vauthors=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 |title=Hereditary early-onset Parkinson's disease caused by mutations in PINK1 |journal=Science |volume=304 |issue=5674 |pages=1158–60 |date=May 2004 |pmid=15087508 |doi=10.1126/science.1096284 |url=}}</ref>
*[[DJ-1]]-associated PD <ref name="pmid12446870">{{cite journal |vauthors=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 |title=Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism |journal=Science |volume=299 |issue=5604 |pages=256–9 |date=January 2003 |pmid=12446870 |doi=10.1126/science.1077209 |url=}}</ref>
====Protein misfolding====
One of the main underlying cause of [[Parkinson's disease|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]].<ref name="pmid12951565">{{cite journal |vauthors=Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K |title=The role of alpha-synuclein in Parkinson's disease: insights from animal models |journal=Nat. Rev. Neurosci. |volume=4 |issue=9 |pages=727–38 |date=September 2003 |pmid=12951565 |doi=10.1038/nrn1199 |url=}}</ref><ref name="pmid26790375">{{cite journal |vauthors=Calo L, Wegrzynowicz M, Santivañez-Perez J, Grazia Spillantini M |title=Synaptic failure and α-synuclein |journal=Mov. Disord. |volume=31 |issue=2 |pages=169–77 |date=February 2016 |pmid=26790375 |doi=10.1002/mds.26479 |url=}}</ref> This [[Mutation|mutations]] lead to unfold [[alpha-synuclein]] and aggregation of insoluble [[protein]] and [[neuronal]] damage. [[Lewy body|Lewy bodies]] which are characteristic of [[Parkinson's disease|PD]] are mostly build from [[alpha-synuclein]] [[protein]].<ref name="pmid9278044">{{cite journal |vauthors=Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M |title=Alpha-synuclein in Lewy bodies |journal=Nature |volume=388 |issue=6645 |pages=839–40 |date=August 1997 |pmid=9278044 |doi=10.1038/42166 |url=}}</ref>
====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|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.<ref name="pmid23580245">{{cite journal |vauthors=Lim KL, Zhang CW |title=Molecular events underlying Parkinson's disease - an interwoven tapestry |journal=Front Neurol |volume=4 |issue= |pages=33 |date=2013 |pmid=23580245 |pmc=3619247 |doi=10.3389/fneur.2013.00033 |url=}}</ref><ref name="pmid23580333">{{cite journal |vauthors=Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E |title=Lysosomal impairment in Parkinson's disease |journal=Mov. Disord. |volume=28 |issue=6 |pages=725–32 |date=June 2013 |pmid=23580333 |pmc=5131721 |doi=10.1002/mds.25462 |url=}}</ref><ref name="pmid24211851">{{cite journal |vauthors=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 |title=Autophagy and apoptosis dysfunction in neurodegenerative disorders |journal=Prog. Neurobiol. |volume=112 |issue= |pages=24–49 |date=January 2014 |pmid=24211851 |doi=10.1016/j.pneurobio.2013.10.004 |url=}}</ref>
====Mitochondrial dysfunction====
The [[drug]] 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an [[Analog (chemistry)|analog]] of mepridine is found to be associated with [[Parkinson's disease|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 [[Parkinson's disease|PD]] patients.<ref name="pmid15377875">{{cite journal |vauthors=Przedborski S, Tieu K, Perier C, Vila M |title=MPTP as a mitochondrial neurotoxic model of Parkinson's disease |journal=J. Bioenerg. Biomembr. |volume=36 |issue=4 |pages=375–9 |date=August 2004 |pmid=15377875 |doi=10.1023/B:JOBB.0000041771.66775.d5 |url=}}</ref><ref name="pmid22446186">{{cite journal |vauthors=Selvaraj S, Sun Y, Watt JA, Wang S, Lei S, Birnbaumer L, Singh BB |title=Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling |journal=J. Clin. Invest. |volume=122 |issue=4 |pages=1354–67 |date=April 2012 |pmid=22446186 |pmc=3314472 |doi=10.1172/JCI61332 |url=}}</ref><ref name="pmid2566813">{{cite journal |vauthors=Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD |title=Mitochondrial complex I deficiency in Parkinson's disease |journal=Lancet |volume=1 |issue=8649 |pages=1269 |date=June 1989 |pmid=2566813 |doi= |url=}}</ref>
====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 [[Parkinson's disease|PD]] patients.<ref name="pmid15155938">{{cite journal |vauthors=Greenamyre JT, Hastings TG |title=Biomedicine. Parkinson's--divergent causes, convergent mechanisms |journal=Science |volume=304 |issue=5674 |pages=1120–2 |date=May 2004 |pmid=15155938 |doi=10.1126/science.1098966 |url=}}</ref><ref name="pmid14645467">{{cite journal |vauthors=Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT |title=Mechanism of toxicity in rotenone models of Parkinson's disease |journal=J. Neurosci. |volume=23 |issue=34 |pages=10756–64 |date=November 2003 |pmid=14645467 |doi= |url=}}</ref> They can also cause protein misfolding by attacking disulfide isomerase through [[nitric oxide]]. Disulfide isomerase is a [[chaperone]] preventing the aggregation of [[proteins]].<ref name="pmid16724068">{{cite journal |vauthors=Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA |title=S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration |journal=Nature |volume=441 |issue=7092 |pages=513–7 |date=May 2006 |pmid=16724068 |doi=10.1038/nature04782 |url=}}</ref>
====Iron metabolism====
Studies showed that impaired [[iron metabolism]] leads to increase amount of [[iron]] in [[substantia nigra]] of [[Parkinson's disease|PD]] patients. One of the underlying [[etiology]] of [[iron]] accommodation in [[Neuron|neuronal cells]] is the absence of [[tau protein]].<ref name="pmid17515544">{{cite journal |vauthors=Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM |title=Individual dopaminergic neurons show raised iron levels in Parkinson disease |journal=Neurology |volume=68 |issue=21 |pages=1820–5 |date=May 2007 |pmid=17515544 |doi=10.1212/01.wnl.0000262033.01945.9a |url=}}</ref><ref name="pmid22266337">{{cite journal |vauthors=Dusek P, Jankovic J, Le W |title=Iron dysregulation in movement disorders |journal=Neurobiol. Dis. |volume=46 |issue=1 |pages=1–18 |date=April 2012 |pmid=22266337 |doi=10.1016/j.nbd.2011.12.054 |url=}}</ref><ref name="pmid22286308">{{cite journal |vauthors=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 |title=Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export |journal=Nat. Med. |volume=18 |issue=2 |pages=291–5 |date=January 2012 |pmid=22286308 |doi=10.1038/nm.2613 |url=}}</ref>
====Immunologic and inflammatory mechanisms====
There are some studies supporting the idea of [[Immunology|immunologic]] mechanisms causing [[Parkinson's disease|PD]].<ref name="pmid19296921">{{cite journal |vauthors=Hirsch EC, Hunot S |title=Neuroinflammation in Parkinson's disease: a target for neuroprotection? |journal=Lancet Neurol |volume=8 |issue=4 |pages=382–97 |date=April 2009 |pmid=19296921 |doi=10.1016/S1474-4422(09)70062-6 |url=}}</ref> In [[Parkinson's disease|PD]] patients there is elevated amounts of [[cyclooxygenase-2]] which is the rate limiting enzyme in [[Prostaglandin E|prostaglandin E2]] synthesis.<ref name="pmid12702778">{{cite journal |vauthors=Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S |title=Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=9 |pages=5473–8 |date=April 2003 |pmid=12702778 |pmc=154369 |doi=10.1073/pnas.0837397100 |url=}}</ref> [[Neuron|Neuronal cell]] death can also occur due to infiltration of [[CD4+ T cells]].<ref name="pmid19104149">{{cite journal |vauthors=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 |title=Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease |journal=J. Clin. Invest. |volume=119 |issue=1 |pages=182–92 |date=January 2009 |pmid=19104149 |pmc=2613467 |doi=10.1172/JCI36470 |url=}}</ref>
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

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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.[15][16][17]

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.[18][19] They can also cause protein misfolding by attacking disulfide isomerase through nitric oxide. Disulfide isomerase is a chaperone preventing the aggregation of proteins.[20]

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.[21][22][23]

Immunologic and inflammatory mechanisms

There are some studies supporting the idea of immunologic mechanisms causing PD.[24] In PD patients there is elevated amounts of cyclooxygenase-2 which is the rate limiting enzyme in prostaglandin E2 synthesis.[25] Neuronal cell death can also occur due to infiltration of CD4+ T cells.[26]

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. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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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