KEGG   PATHWAY: ko05012
ko05012                     Pathway                                
Parkinson disease
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). Both environmental factors and mutations in familial PD-linked genes such as SNCA, Parkin, DJ-1, PINK1 and LRRK2 are associated with PD pathogenesis. These pathogenic mutations and environmental factors are known to cause disease due to oxidative stress, intracellular Ca2+ homeostasis impairment, mitochondrial dysfunctions and altered protein handling compromising key roles of DA neuronal function and survival. The demise of DA neurons located in the SNc leads to a drop in the dopaminergic input to the striatum, which is hypothesized to impede movement by inducing hypo and hyper activity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively.
Human Diseases; Neurodegenerative disease
Pathway map
ko05012  Parkinson disease

H00057  Parkinson disease
K04266  adenosine receptor A2a
K04633  guanine nucleotide-binding protein G(olf) subunit alpha
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K04145  dopamine receptor D2
K04630  guanine nucleotide-binding protein G(i) subunit alpha
K08045  adenylate cyclase 5 [EC:]
K04345  protein kinase A [EC:]
K04144  dopamine receptor D1
K03178  ubiquitin-activating enzyme E1 [EC:]
K10698  ubiquitin-activating enzyme E1-like [EC:]
K02927  ubiquitin-large subunit ribosomal protein L40e
K02977  ubiquitin-small subunit ribosomal protein S27Ae
K04551  ubiquitin B
K08770  ubiquitin C
K04552  ubiquitin-conjugating enzyme E2 L3 [EC:]
K04553  ubiquitin/ISG15-conjugating enzyme E2 L6 [EC:]
K04554  ubiquitin-conjugating enzyme E2 J2 [EC:]
K10578  ubiquitin-conjugating enzyme E2 J1 [EC:]
K04555  ubiquitin-conjugating enzyme E2 G2 [EC:]
K10575  ubiquitin-conjugating enzyme E2 G1 [EC:]
K04556  parkin [EC:]
K04528  alpha-synuclein
K04243  prosaposin receptor
K04557  septin 5
K04558  synphilin-1
K02730  20S proteasome subunit alpha 1 [EC:]
K02726  20S proteasome subunit alpha 2 [EC:]
K02728  20S proteasome subunit alpha 3 [EC:]
K02731  20S proteasome subunit alpha 4 [EC:]
K02729  20S proteasome subunit alpha 5 [EC:]
K02725  20S proteasome subunit alpha 6 [EC:]
K02727  20S proteasome subunit alpha 7 [EC:]
K02738  20S proteasome subunit beta 1 [EC:]
K02739  20S proteasome subunit beta 2 [EC:]
K02735  20S proteasome subunit beta 3 [EC:]
K02734  20S proteasome subunit beta 4 [EC:]
K02737  20S proteasome subunit beta 5 [EC:]
K02732  20S proteasome subunit beta 6 [EC:]
K02736  20S proteasome subunit beta 7 [EC:]
K03061  26S proteasome regulatory subunit T1
K03062  26S proteasome regulatory subunit T2
K03063  26S proteasome regulatory subunit T3
K03064  26S proteasome regulatory subunit T4
K03065  26S proteasome regulatory subunit T5
K03066  26S proteasome regulatory subunit T6
K03028  26S proteasome regulatory subunit N1
K03032  26S proteasome regulatory subunit N2
K03033  26S proteasome regulatory subunit N3
K06693  26S proteasome regulatory subunit N4
K03035  26S proteasome regulatory subunit N5
K03036  26S proteasome regulatory subunit N6
K03037  26S proteasome regulatory subunit N7
K03038  26S proteasome regulatory subunit N8
K03039  26S proteasome regulatory subunit N9
K03029  26S proteasome regulatory subunit N10
K03030  26S proteasome regulatory subunit N11
K03031  26S proteasome regulatory subunit N12
K06691  26S proteasome regulatory subunit N13
K10881  26 proteasome complex subunit DSS1
K05611  ubiquitin carboxyl-terminal hydrolase L1 [EC:]
K02183  calmodulin
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:]
K04380  microtubule-associated protein tau
K04963  ryanodine receptor 3
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:]
K09490  endoplasmic reticulum chaperone BiP [EC:]
K09054  cyclic AMP-dependent transcription factor ATF-6 alpha
K04452  DNA damage-inducible transcript 3
K08852  serine/threonine-protein kinase/endoribonuclease IRE1 [EC: 3.1.26.-]
K09027  X box-binding protein 1
K08860  eukaryotic translation initiation factor 2-alpha kinase 3 [EC:]
K03237  translation initiation factor 2 subunit 1
K04374  cyclic AMP-dependent transcription factor ATF-4
K00501  tyrosine 3-monooxygenase [EC:]
K00274  monoamine oxidase [EC:]
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
K21398  natural resistance-associated macrophage protein 2
K14709  solute carrier family 39 (zinc transporter), member 1/2/3
K14710  solute carrier family 39 (zinc transporter), member 4
K14711  solute carrier family 39 (zinc transporter), member 5
K14712  solute carrier family 39 (zinc transporter), member 6
K14713  solute carrier family 39 (zinc transporter), member 7
K14714  solute carrier family 39 (zinc transporter), member 8
K14715  solute carrier family 39 (zinc transporter), member 9
K14716  solute carrier family 39 (zinc transporter), member 10
K14717  solute carrier family 39 (zinc transporter), member 11
K14718  solute carrier family 39 (zinc transporter), member 12
K14719  solute carrier family 39 (zinc transporter), member 13
K14720  solute carrier family 39 (zinc transporter), member 14
K03878  NADH-ubiquinone oxidoreductase chain 1 [EC:]
K03879  NADH-ubiquinone oxidoreductase chain 2 [EC:]
K03880  NADH-ubiquinone oxidoreductase chain 3 [EC:]
K03881  NADH-ubiquinone oxidoreductase chain 4 [EC:]
K03882  NADH-ubiquinone oxidoreductase chain 4L [EC:]
K03883  NADH-ubiquinone oxidoreductase chain 5 [EC:]
K03884  NADH-ubiquinone oxidoreductase chain 6 [EC:]
K03942  NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:]
K03943  NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:]
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, acyl-carrier protein
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:]
K03935  NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:]
K03936  NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:]
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:]
K03941  NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:]
K03967  NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234  succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:]
K00235  succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:]
K00236  succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237  succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411  ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:]
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:]
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:]
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
K05688  PTEN induced putative kinase 1 [EC:]
K20858  calcium uniporter protein, mitochondrial
K08844  leucine-rich repeat kinase 2 [EC:]
K08669  HtrA serine peptidase 2 [EC:]
K09488  TNF receptor-associated protein 1
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:]
K08738  cytochrome c
K02084  apoptotic protease-activating factor
K04399  caspase 9 [EC:]
K02187  caspase 3 [EC:]
K05687  protein DJ-1 [EC:]
K04570  Bcl-2-like 1 (apoptosis regulator Bcl-X)
K02159  apoptosis regulator BAX
K21356  mitofusin 1 [EC:3.6.5.-]
K06030  mitofusin 2 [EC:3.6.5.-]
K10396  kinesin family member 5
K10407  kinesin light chain
K07374  tubulin alpha
K07375  tubulin beta
K04451  tumor protein p53
K21278  dual specificity protein phosphatase 1 [EC:]
K05638  nuclear factor erythroid 2-related factor 2
K03671  thioredoxin
K02308  death-associated protein 6
K04426  mitogen-activated protein kinase kinase kinase 5 [EC:]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K04565  superoxide dismutase, Cu-Zn family [EC:]
K10456  kelch-like protein 19
C00002  ATP
C00007  Oxygen
C00008  ADP
C00009  Orthophosphate
C00013  Diphosphate
C00020  AMP
C00027  Hydrogen peroxide
C00034  Manganese
C00076  Calcium cation
C00082  L-Tyrosine
C00165  Diacylglycerol
C00212  Adenosine
C00355  3,4-Dihydroxy-L-phenylalanine
C00575  3',5'-Cyclic AMP
C00704  Superoxide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C03758  Dopamine
C04043  3,4-Dihydroxyphenylacetaldehyde
C04599  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
C07593  Rotenone
C11310  1-Methyl-4-phenylpyridinium
C14701  Paraquat
C15231  Maneb
C16844  Hydroxyl radical
C17755  Dopamine quinone
C22381  Reactive oxygen species
Abou-Sleiman PM, Muqit MM, Wood NW
Expanding insights of mitochondrial dysfunction in Parkinson's disease.
Nat Rev Neurosci 7:207-19 (2006)
Lim KL, Lim TM
Molecular mechanisms of neurodegeneration in Parkinson's disease: clues from Mendelian syndromes.
IUBMB Life 55:315-22 (2003)
Bobela W, Aebischer P, Schneider BL
Alphalpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson's Disease.
Biomolecules 5:2675-700 (2015)
Eriksen JL, Wszolek Z, Petrucelli L
Molecular pathogenesis of Parkinson disease.
Arch Neurol 62:353-7 (2005)
Olanow CW, McNaught KS
Ubiquitin-proteasome system and Parkinson's disease.
Mov Disord 21:1806-23 (2006)
Lim KL, Tan JM
Role of the ubiquitin proteasome system in Parkinson's disease.
BMC Biochem 8 Suppl 1:S13 (2007)
Maiti P, Manna J, Dunbar GL
Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments.
Transl Neurodegener 6:28 (2017)
Dev KK, van der Putten H, Sommer B, Rovelli G
Part I: parkin-associated proteins and Parkinson's disease.
Neuropharmacology 45:1-13 (2003)
Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G
Missing pieces in the Parkinson's disease puzzle.
Nat Med 16:653-61 (2010)
Cali T, Ottolini D, Brini M
Calcium signaling in Parkinson's disease.
Cell Tissue Res 357:439-54 (2014)
Bezprozvanny I
Calcium signaling and neurodegenerative diseases.
Trends Mol Med 15:89-100 (2009)
Zaichick SV, McGrath KM, Caraveo G
The role of Ca(2+) signaling in Parkinson's disease.
Dis Model Mech 10:519-535 (2017)
Ludtmann MHR, Abramov AY
Mitochondrial calcium imbalance in Parkinson's disease.
Neurosci Lett 663:86-90 (2018)
Sandebring A, Dehvari N, Perez-Manso M, Thomas KJ, Karpilovski E, Cookson MR, Cowburn RF, Cedazo-Minguez A
Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling.
FEBS J 276:5041-52 (2009)
Mercado G, Valdes P, Hetz C
An ERcentric view of Parkinson's disease.
Trends Mol Med 19:165-75 (2013)
Mercado G, Castillo V, Soto P, Sidhu A
ER stress and Parkinson's disease: Pathological inputs that converge into the secretory pathway.
Brain Res 1648:626-632 (2016)
Tsujii S, Ishisaka M, Hara H
Modulation of endoplasmic reticulum stress in Parkinson's disease.
Eur J Pharmacol 765:154-6 (2015)
Shah A, Chao J, Legido-Quigley C, Chang RC
Oxyresveratrol exerts ATF4- and Grp78-mediated neuroprotection against endoplasmic reticulum stress in experimental Parkinson's disease.
Nutr Neurosci 1-16 (2019)
Segura-Aguilar J, Paris I, Munoz P, Ferrari E, Zecca L, Zucca FA
Protective and toxic roles of dopamine in Parkinson's disease.
J Neurochem 129:898-915 (2014)
Jesko H, Lenkiewicz AM, Wilkaniec A, Adamczyk A
The interplay between parkin and alpha-synuclein; possible implications for the pathogenesis of Parkinson's disease.
Acta Neurobiol Exp (Wars) 79:276-289 (2019)
Perez RG, Hastings TG
Could a loss of alpha-synuclein function put dopaminergic neurons at risk?
J Neurochem 89:1318-24 (2004)
Segura-Aguilar J
A new mechanism for protection of dopaminergic neurons mediated by astrocytes.
Neural Regen Res 10:1225-7 (2015)
Bose A, Beal MF
Mitochondrial dysfunction in Parkinson's disease.
J Neurochem 139 Suppl 1:216-231 (2016)
Cieri D, Brini M, Cali T
Emerging (and converging) pathways in Parkinson's disease: keeping mitochondrial wellness.
Biochem Biophys Res Commun 483:1020-1030 (2017)
Mack JM, Schamne MG, Sampaio TB, Pertile RA, Fernandes PA, Markus RP, Prediger RD
Melatoninergic System in Parkinson's Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms.
Oxid Med Cell Longev 2016:3472032 (2016)
Cali T, Ottolini D, Brini M
Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease.
Biofactors 37:228-40 (2011)
Gaki GS, Papavassiliou AG
Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease.
Neuromolecular Med 16:217-30 (2014)
Franco-Iborra S, Vila M, Perier C
The Parkinson Disease Mitochondrial Hypothesis: Where Are We at?
Neuroscientist 22:266-77 (2016)
de Vries RL, Przedborski S
Mitophagy and Parkinson's disease: be eaten to stay healthy.
Mol Cell Neurosci 55:37-43 (2013)
Deas E, Wood NW, Plun-Favreau H
Mitophagy and Parkinson's disease: the PINK1-parkin link.
Biochim Biophys Acta 1813:623-33 (2011)
Pickrell AM, Youle RJ
The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease.
Neuron 85:257-73 (2015)
Truban D, Hou X, Caulfield TR, Fiesel FC, Springer W
PINK1, Parkin, and Mitochondrial Quality Control: What can we Learn about Parkinson's Disease Pathobiology?
J Parkinsons Dis 7:13-29 (2017)
Biosa A, Sandrelli F, Beltramini M, Greggio E, Bubacco L, Bisaglia M
Recent findings on the physiological function of DJ-1: Beyond Parkinson's disease.
Neurobiol Dis 108:65-72 (2017)
Oh SE, Mouradian MM
Regulation of Signal Transduction by DJ-1.
Adv Exp Med Biol 1037:97-131 (2017)
Dolgacheva LP, Berezhnov AV, Fedotova EI, Zinchenko VP, Abramov AY
Role of DJ-1 in the mechanism of pathogenesis of Parkinson's disease.
J Bioenerg Biomembr 51:175-188 (2019)
Melo TQ, Copray SJCVM, Ferrari MFR
Alpha-Synuclein Toxicity on Protein Quality Control, Mitochondria and Endoplasmic Reticulum.
Neurochem Res 43:2212-2223 (2018)
Zhai S, Shen W, Graves SM, Surmeier DJ
Dopaminergic modulation of striatal function and Parkinson's disease.
J Neural Transm (Vienna) 126:411-422 (2019)
Parker JG, Marshall JD, Ahanonu B, Wu YW, Kim TH, Grewe BF, Zhang Y, Li JZ, Ding JB, Ehlers MD, Schnitzer MJ
Diametric neural ensemble dynamics in parkinsonian and dyskinetic states.
Nature 557:177-182 (2018)
ko00190  Oxidative phosphorylation
ko00350  Tyrosine metabolism
ko03050  Proteasome
ko04020  Calcium signaling pathway
ko04120  Ubiquitin mediated proteolysis
ko04137  Mitophagy - animal
ko04141  Protein processing in endoplasmic reticulum
ko04210  Apoptosis
ko04728  Dopaminergic synapse

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