KEGG   PATHWAY: ko05012Help
Entry
ko05012                     Pathway                                

Name
Parkinson disease
Description
Parkinson disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Mutations in alpha-synuclein, UCHL1 (a ubiquitin carboxy-terminal hydrolase L1), parkin, DJ1 (a parkin-associated protein involved with oxidative stress), and PINK1 (a putative serine threonine kinase) are known to cause early-onset PD. Mutations or altered expression of these proteins contributes to the damage and subsequent loss of DA neurons through common mechanisms that result in proteasome dysfunction, mitochondrial impairment, and oxidative stress. The demise of DA neurons located in the SNc leads to a drop in the dopaminergic input to the striatum. This results in a reduced activation of the direct pathway and in a disinhibition of the indirect pathway, which is associated with the elevation of adenosine A2A receptor transmission. Such unbalanced activity of the striatal output pathway is at the basis of the motor impairment observed in PD.
Class
Human Diseases; Neurodegenerative diseases
BRITE hierarchy
Pathway map
ko05012  Parkinson disease
ko05012

Ortholog table
Disease
H00057  Parkinson disease
Orthology
K04266  adenosine receptor A2a
K04633  guanine nucleotide-binding protein G(olf) subunit alpha
K04145  dopamine receptor D2
K04630  guanine nucleotide-binding protein G(i) subunit alpha
K08045  adenylate cyclase 5 [EC:4.6.1.1]
K04345  protein kinase A [EC:2.7.11.11]
K04144  dopamine receptor D1
K03178  ubiquitin-activating enzyme E1 [EC:6.2.1.45]
K10698  ubiquitin-activating enzyme E1-like [EC:6.2.1.45]
K04551  ubiquitin B
K04552  ubiquitin-conjugating enzyme E2 L3 [EC:2.3.2.23]
K04553  ubiquitin-conjugating enzyme E2 L6 [EC:2.3.2.23]
K04554  ubiquitin-conjugating enzyme E2 J2 [EC:2.3.2.23]
K10578  ubiquitin-conjugating enzyme E2 J1 [EC:2.3.2.23]
K04555  ubiquitin-conjugating enzyme E2 G2 [EC:2.3.2.23]
K10575  ubiquitin-conjugating enzyme E2 G1 [EC:2.3.2.23]
K04556  parkin [EC:2.3.2.31]
K04528  alpha-synuclein
K04243  prosaposin receptor
K04557  septin 5
K04558  synuclein, alpha interacting protein (synphilin)
K05611  ubiquitin carboxyl-terminal hydrolase L1 [EC:3.4.19.12]
K00501  tyrosine 3-monooxygenase [EC:1.14.16.2]
K05036  solute carrier family 6 (neurotransmitter transporter, dopamine) member 3
K08155  MFS transporter, DHA1 family, solute carrier family 18 (vesicular amine transporter), member 1/2
K03878  NADH-ubiquinone oxidoreductase chain 1 [EC:7.1.1.2]
K03879  NADH-ubiquinone oxidoreductase chain 2 [EC:7.1.1.2]
K03880  NADH-ubiquinone oxidoreductase chain 3 [EC:7.1.1.2]
K03881  NADH-ubiquinone oxidoreductase chain 4 [EC:7.1.1.2]
K03882  NADH-ubiquinone oxidoreductase chain 4L [EC:7.1.1.2]
K03883  NADH-ubiquinone oxidoreductase chain 5 [EC:7.1.1.2]
K03884  NADH-ubiquinone oxidoreductase chain 6 [EC:7.1.1.2]
K03942  NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:1.6.99.3 7.1.1.2]
K03943  NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:1.6.99.3 7.1.1.2]
K03944  NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955  NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1
K03956  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K11352  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K03957  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K11351  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K03934  NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:1.6.99.3 7.1.1.2]
K03935  NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:1.6.99.3 7.1.1.2]
K03936  NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:1.6.99.3 7.1.1.2]
K03937  NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938  NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939  NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940  NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:1.6.99.3 7.1.1.2]
K03941  NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:1.6.99.3 7.1.1.2]
K03967  NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234  succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:1.3.5.1]
K00235  succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:1.3.5.1]
K00236  succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237  succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411  ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:7.1.1.8]
K00412  ubiquinol-cytochrome c reductase cytochrome b subunit
K00413  ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414  ubiquinol-cytochrome c reductase core subunit 1
K00415  ubiquinol-cytochrome c reductase core subunit 2
K00416  ubiquinol-cytochrome c reductase subunit 6
K00417  ubiquinol-cytochrome c reductase subunit 7
K00418  ubiquinol-cytochrome c reductase subunit 8
K00419  ubiquinol-cytochrome c reductase subunit 9
K00420  ubiquinol-cytochrome c reductase subunit 10
K02262  cytochrome c oxidase subunit 3
K02256  cytochrome c oxidase subunit 1 [EC:1.9.3.1]
K02261  cytochrome c oxidase subunit 2
K02263  cytochrome c oxidase subunit 4
K02264  cytochrome c oxidase subunit 5a
K02265  cytochrome c oxidase subunit 5b
K02266  cytochrome c oxidase subunit 6a
K02267  cytochrome c oxidase subunit 6b
K02268  cytochrome c oxidase subunit 6c
K02270  cytochrome c oxidase subunit 7a
K02271  cytochrome c oxidase subunit 7b
K02272  cytochrome c oxidase subunit 7c
K02273  cytochrome c oxidase subunit 8
K02132  F-type H+-transporting ATPase subunit alpha
K02133  F-type H+-transporting ATPase subunit beta [EC:7.1.2.2]
K02136  F-type H+-transporting ATPase subunit gamma
K02134  F-type H+-transporting ATPase subunit delta
K02135  F-type H+-transporting ATPase subunit epsilon
K02126  F-type H+-transporting ATPase subunit a
K02127  F-type H+-transporting ATPase subunit b
K02128  F-type H+-transporting ATPase subunit c
K02138  F-type H+-transporting ATPase subunit d
K02137  F-type H+-transporting ATPase subunit O
K02131  F-type H+-transporting ATPase subunit 6
K02125  F-type H+-transporting ATPase subunit 8
K08844  leucine-rich repeat kinase 2 [EC:2.7.11.1]
K05688  PTEN induced putative kinase 1 [EC:2.7.11.1]
K05687  protein DJ-1 [EC:3.5.1.124]
K08669  HtrA serine peptidase 2 [EC:3.4.21.108]
K05862  voltage-dependent anion channel protein 1
K15040  voltage-dependent anion channel protein 2
K15041  voltage-dependent anion channel protein 3
K05863  solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
K09565  peptidyl-prolyl isomerase F (cyclophilin D) [EC:5.2.1.8]
K08738  cytochrome c
K02084  apoptotic protease-activating factor
K04399  caspase 9 [EC:3.4.22.62]
K02187  caspase 3 [EC:3.4.22.56]
Compound
C00002  ATP
C00008  ADP
C00009  Orthophosphate
C00013  Diphosphate
C00020  AMP
C00027  Hydrogen peroxide
C00082  L-Tyrosine
C00212  Adenosine
C00355  3,4-Dihydroxy-L-phenylalanine
C00575  3',5'-Cyclic AMP
C00704  O2.-
C03758  Dopamine
C04599  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
C07593  Rotenone
C11310  1-Methyl-4-phenylpyridinium
Reference
  Authors
Thomas B, Beal MF
  Title
Parkinson's disease.
  Journal
Hum Mol Genet 16 Spec No. 2:R183-94 (2007)
DOI:10.1093/hmg/ddm159
Reference
  Authors
Lim KL, Lim TM
  Title
Molecular mechanisms of neurodegeneration in Parkinson's disease: clues from Mendelian syndromes.
  Journal
IUBMB Life 55:315-22 (2003)
DOI:10.1080/1521654031000153030
Reference
  Authors
Moore DJ, West AB, Dawson VL, Dawson TM
  Title
Molecular pathophysiology of Parkinson's disease.
  Journal
Annu Rev Neurosci 28:57-87 (2005)
DOI:10.1146/annurev.neuro.28.061604.135718
Reference
  Authors
Abou-Sleiman PM, Muqit MM, Wood NW
  Title
Expanding insights of mitochondrial dysfunction in Parkinson's disease.
  Journal
Nat Rev Neurosci 7:207-19 (2006)
DOI:10.1038/nrn1868
Reference
  Authors
Mizuno Y, Hattori N, Kubo S, Sato S, Nishioka K, Hatano T, Tomiyama H, Funayama M, Machida Y, Mochizuki H
  Title
Progress in the pathogenesis and genetics of Parkinson's disease.
  Journal
Philos Trans R Soc Lond B Biol Sci 363:2215-27 (2008)
DOI:10.1098/rstb.2008.2273
Reference
  Authors
Gandhi S, Wood NW
  Title
Molecular pathogenesis of Parkinson's disease.
  Journal
Hum Mol Genet 14 Spec No. 2:2749-2755 (2005)
DOI:10.1093/hmg/ddi308
Reference
  Authors
Lotharius J, Brundin P
  Title
Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein.
  Journal
Nat Rev Neurosci 3:932-42 (2002)
DOI:10.1038/nrn983
Reference
  Authors
Eriksen JL, Wszolek Z, Petrucelli L
  Title
Molecular pathogenesis of Parkinson disease.
  Journal
Arch Neurol 62:353-7 (2005)
DOI:10.1001/archneur.62.3.353
Reference
  Authors
Sidhu A, Wersinger C, Vernier P
  Title
Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse?
  Journal
FASEB J 18:637-47 (2004)
DOI:10.1096/fj.03-1112rev
Reference
  Authors
Sidhu A, Wersinger C, Moussa CE, Vernier P
  Title
The role of alpha-synuclein in both neuroprotection and neurodegeneration.
  Journal
Ann N Y Acad Sci 1035:250-70 (2004)
DOI:10.1196/annals.1332.016
Reference
  Authors
Dauer W, Przedborski S
  Title
Parkinson's disease: mechanisms and models.
  Journal
Neuron 39:889-909 (2003)
DOI:10.1016/S0896-6273(03)00568-3
Reference
  Authors
Feany MB
  Title
New genetic insights into Parkinson's disease.
  Journal
N Engl J Med 351:1937-40 (2004)
DOI:10.1056/NEJMp048263
Reference
  Authors
Beal MF
  Title
Experimental models of Parkinson's disease.
  Journal
Nat Rev Neurosci 2:325-34 (2001)
DOI:10.1038/35072550
Reference
  Authors
Corti O, Hampe C, Darios F, Ibanez P, Ruberg M, Brice A
  Title
Parkinson's disease: from causes to mechanisms.
  Journal
C R Biol 328:131-42 (2005)
DOI:10.1016/j.crvi.2004.10.009
Reference
  Authors
Vila M, Ramonet D, Perier C
  Title
Mitochondrial alterations in Parkinson's disease: new clues.
  Journal
J Neurochem 107:317-28 (2008)
DOI:10.1111/j.1471-4159.2008.05604.x
Reference
  Authors
Vila M, Przedborski S
  Title
Targeting programmed cell death in neurodegenerative diseases.
  Journal
Nat Rev Neurosci 4:365-75 (2003)
DOI:10.1038/nrn1100
Reference
  Authors
Calabresi P, Di Filippo M, Gallina A, Wang Y, Stankowski JN, Picconi B, Dawson VL, Dawson TM
  Title
New synaptic and molecular targets for neuroprotection in Parkinson's disease.
  Journal
Mov Disord 28:51-60 (2013)
DOI:10.1002/mds.25096
Reference
  Authors
Nishi A, Kuroiwa M, Shuto T
  Title
Mechanisms for the modulation of dopamine d(1) receptor signaling in striatal neurons.
  Journal
Front Neuroanat 5:43 (2011)
DOI:10.3389/fnana.2011.00043
Reference
  Authors
Hara M, Fukui R, Hieda E, Kuroiwa M, Bateup HS, Kano T, Greengard P, Nishi A
  Title
Role of adrenoceptors in the regulation of dopamine/DARPP-32 signaling in neostriatal neurons.
  Journal
J Neurochem 113:1046-59 (2010)
DOI:10.1111/j.1471-4159.2010.06668.x
LinkDB All DBs

DBGET integrated database retrieval system