KEGG PATHWAY: ko05012

PATHWAY: ko05012

Entry

ko05012 Pathway

Name

Parkinson's disease

Description

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra. 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. These pathogenic mutations are associated with disease through pathogenic pathways that may commonly lead proteasome dysfunction, mitochondrial impairment, and oxidative stress. Point mutations in alpha-synuclein lead to excessive intracellular accumulation and protofibril formation. Decrease in the amount of soluble alpha-synuclein tends to increase free cytoplasmic dopamine and the formation of reactive oxygen species (ROS). Modification of parkin and UCHL1 are associated with the ubiquitin-proteasome system pathway and may increase proteotoxic stress. Mutations in parkin, DJ1, and PINK1 may alter mitochondiral activity, potentially impairing proteasomal function. Environmental toxins such as N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone can cause mitochondrial dysfunction and oxidative stress.

Class

Human Diseases; Neurodegenerative diseases

Pathway map

ko05012

Parkinson's disease

Disease

H00057	Parkinson's disease (PD)
H00473	Mitochondrial respiratory chain deficiencies (MRCD)
H00831	Primary dystonia

Orthology

K03178	ubiquitin-activating enzyme E1 [EC:6.3.2.19]
K10698	ubiquitin-activating enzyme E1-like [EC:6.3.2.19]
K04551	ubiquitin B
K04552	ubiquitin-conjugating enzyme E2 L3 [EC:6.3.2.19]
K04553	ubiquitin-conjugating enzyme E2 L6 [EC:6.3.2.19]
K04554	ubiquitin-conjugating enzyme E2 J2 [EC:6.3.2.19]
K10578	ubiquitin-conjugating enzyme E2 J1 [EC:6.3.2.19]
K04555	ubiquitin-conjugating enzyme E2 G2 [EC:6.3.2.19]
K10575	ubiquitin-conjugating enzyme E2 G1 [EC:6.3.2.19]
K04556	parkin [EC:6.3.2.19]
K04528	synuclein, alpha (non A4 component of amyloid precursor)
K04243	G protein-coupled receptor 37 (endothelin receptor type B-like)
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:1.6.5.3]
K03879	NADH-ubiquinone oxidoreductase chain 2 [EC:1.6.5.3]
K03880	NADH-ubiquinone oxidoreductase chain 3 [EC:1.6.5.3]
K03881	NADH-ubiquinone oxidoreductase chain 4 [EC:1.6.5.3]
K03882	NADH-ubiquinone oxidoreductase chain 4L [EC:1.6.5.3]
K03883	NADH-ubiquinone oxidoreductase chain 5 [EC:1.6.5.3]
K03884	NADH-ubiquinone oxidoreductase chain 6 [EC:1.6.5.3]
K03942	NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:1.6.99.3 1.6.5.3]
K03943	NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:1.6.99.3 1.6.5.3]
K03944	NADH dehydrogenase (ubiquinone) flavoprotein 3 [EC:1.6.99.3 1.6.5.3]
K03945	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 1 [EC:1.6.99.3 1.6.5.3]
K03946	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 2 [EC:1.6.99.3 1.6.5.3]
K03947	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 3 [EC:1.6.99.3 1.6.5.3]
K03948	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 [EC:1.6.99.3 1.6.5.3]
K03949	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 5 [EC:1.6.99.3 1.6.5.3]
K03950	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 6 [EC:1.6.99.3 1.6.5.3]
K03951	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 7 [EC:1.6.99.3 1.6.5.3]
K03952	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 8 [EC:1.6.99.3 1.6.5.3]
K03953	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 9 [EC:1.6.99.3 1.6.5.3]
K03954	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10 [EC:1.6.99.3 1.6.5.3]
K03955	NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1 [EC:1.6.99.3 1.6.5.3]
K03956	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 11 [EC:1.6.5.3]
K11352	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 12 [EC:1.6.99.3 1.6.5.3]
K11353	NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 13 [EC:1.6.99.3 1.6.5.3]
K03957	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 1 [EC:1.6.99.3 1.6.5.3]
K03958	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 2 [EC:1.6.99.3 1.6.5.3]
K03959	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 3 [EC:1.6.99.3 1.6.5.3]
K03960	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 4 [EC:1.6.99.3 1.6.5.3]
K03961	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 5 [EC:1.6.99.3 1.6.5.3]
K03962	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 6 [EC:1.6.99.3 1.6.5.3]
K03963	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 7 [EC:1.6.99.3 1.6.5.3]
K03964	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 [EC:1.6.99.3 1.6.5.3]
K03965	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 9 [EC:1.6.99.3 1.6.5.3]
K03966	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 10 [EC:1.6.99.3 1.6.5.3]
K11351	NADH dehydrogenase (ubiquinone) 1 beta subcomplex 11 [EC:1.6.99.3 1.6.5.3]
K03934	NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:1.6.99.3 1.6.5.3]
K03935	NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:1.6.99.3 1.6.5.3]
K03936	NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:1.6.99.3 1.6.5.3]
K03937	NADH dehydrogenase (ubiquinone) Fe-S protein 4 [EC:1.6.99.3 1.6.5.3]
K03938	NADH dehydrogenase (ubiquinone) Fe-S protein 5 [EC:1.6.99.3 1.6.5.3]
K03939	NADH dehydrogenase (ubiquinone) Fe-S protein 6 [EC:1.6.99.3 1.6.5.3]
K03940	NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:1.6.99.3 1.6.5.3]
K03941	NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:1.6.99.3 1.6.5.3]
K03967	NADH dehydrogenase (ubiquinone) 1 subcomplex unknown 1 [EC:1.6.99.3 1.6.5.3]
K03968	NADH dehydrogenase (ubiquinone) 1 subcomplex unknown 2 [EC:1.6.99.3 1.6.5.3]
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:1.10.2.2]
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 [EC:3.6.3.14]
K02133	F-type H+-transporting ATPase subunit beta [EC:3.6.3.14]
K02136	F-type H+-transporting ATPase subunit gamma [EC:3.6.3.14]
K02134	F-type H+-transporting ATPase subunit delta [EC:3.6.3.14]
K02135	F-type H+-transporting ATPase subunit epsilon [EC:3.6.3.14]
K02126	F-type H+-transporting ATPase subunit a [EC:3.6.3.14]
K02127	F-type H+-transporting ATPase subunit b [EC:3.6.3.14]
K02128	F-type H+-transporting ATPase subunit c [EC:3.6.3.14]
K02138	F-type H+-transporting ATPase subunit d [EC:3.6.3.14]
K02137	F-type H+-transporting ATPase oligomycin sensitivity conferral protein [EC:3.6.3.14]
K02131	F-type H+-transporting ATPase subunit 6 [EC:3.6.3.14]
K02125	F-type H+-transporting ATPase subunit 8 [EC:3.6.3.14]
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
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
C00355	3,4-Dihydroxy-L-phenylalanine
C00704	O2.-
C03758	Dopamine
C04599	1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
C07593	Rotenone
C11310	1-Methyl-4-phenylpyridinium

Reference

PMID:17911161

Authors

Thomas B, Beal MF

Title

Parkinson's disease.

Journal

Hum Mol Genet 16 Spec No. 2:R183-94 (2007)

Reference

PMID:12938733

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)

Reference

PMID:16022590

Authors

Moore DJ, West AB, Dawson VL, Dawson TM

Title

Molecular pathophysiology of Parkinson's disease.

Journal

Annu Rev Neurosci 28:57-87 (2005)

Reference

PMID:16495942

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)

Reference

PMID:18426756

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)

Reference

PMID:16278972

Authors

Gandhi S, Wood NW

Title

Molecular pathogenesis of Parkinson's disease.

Journal

Hum Mol Genet 14 Spec No. 2:2749-2755 (2005)

Reference

PMID:12461550

Authors

Lotharius J, Brundin P

Title

Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein.

Journal

Nat Rev Neurosci 3:932-42 (2002)

Reference

PMID:15767499

Authors

Eriksen JL, Wszolek Z, Petrucelli L

Title

Molecular pathogenesis of Parkinson disease.

Journal

Arch Neurol 62:353-7 (2005)

Reference

PMID:15054086

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)

Reference

PMID:15681812

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)

Reference

PMID:12971891

Authors

Dauer W, Przedborski S

Title

Parkinson's disease: mechanisms and models.

Journal

Neuron 39:889-909 (2003)

Reference

PMID:15525720

Authors

Feany MB

Title

New genetic insights into Parkinson's disease.

Journal

N Engl J Med 351:1937-40 (2004)

Reference

PMID:11331916

Authors

Beal MF

Title

Experimental models of Parkinson's disease.

Journal

Nat Rev Neurosci 2:325-34 (2001)

Reference

PMID:15770999

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)

Reference

PMID:18680555

Authors

Vila M, Ramonet D, Perier C

Title

Mitochondrial alterations in Parkinson's disease: new clues.

Journal

J Neurochem 107:317-28 (2008)

Reference

PMID:12728264

Authors

Vila M, Przedborski S

Title

Targeting programmed cell death in neurodegenerative diseases.

Journal

Nat Rev Neurosci 4:365-75 (2003)

All links

Ontology (1)   
   KEGG BRITE (1)   
Pathway (2)   
   KEGG PATHWAY (1)   
   BioSystems (1)   
Disease (3)   
   KEGG DISEASE (3)   
Chemical substance (13)   
   KEGG COMPOUND (13)   
Chemical reaction (14)   
   KEGG ENZYME (14)   
Gene (115)   
   KEGG ORTHOLOGY (115)   
Literature (16)   
   PubMed (16)   
All databases (164)   

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