KEGG PATHWAY: hsa05012

PATHWAY: hsa05012

Entry

hsa05012 Pathway

Name

Parkinson's disease - Homo sapiens (human)

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

hsa05012

Parkinson's disease

Disease

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

Drug

D10014

Ioflupane I 123 (USAN)

Organism

Homo sapiens (human) [GN:hsa]

Gene

7317	UBA1; ubiquitin-like modifier activating enzyme 1 [KO:K03178] [EC:6.3.2.19]
7318	UBA7; ubiquitin-like modifier activating enzyme 7 [KO:K10698] [EC:6.3.2.19]
7314	UBB; ubiquitin B [KO:K04551]
7332	UBE2L3; ubiquitin-conjugating enzyme E2L 3 [KO:K04552] [EC:6.3.2.19]
9246	UBE2L6; ubiquitin-conjugating enzyme E2L 6 [KO:K04553] [EC:6.3.2.19]
118424	UBE2J2; ubiquitin-conjugating enzyme E2, J2 [KO:K04554] [EC:6.3.2.19]
51465	UBE2J1; ubiquitin-conjugating enzyme E2, J1 [KO:K10578] [EC:6.3.2.19]
7327	UBE2G2; ubiquitin-conjugating enzyme E2G 2 [KO:K04555] [EC:6.3.2.19]
7326	UBE2G1; ubiquitin-conjugating enzyme E2G 1 [KO:K10575] [EC:6.3.2.19]
5071	PARK2; parkinson protein 2, E3 ubiquitin protein ligase (parkin) [KO:K04556] [EC:6.3.2.19]
6622	SNCA; synuclein, alpha (non A4 component of amyloid precursor) [KO:K04528]
2861	GPR37; G protein-coupled receptor 37 (endothelin receptor type B-like) [KO:K04243]
5413	SEPT5; septin 5 [KO:K04557]
9627	SNCAIP; synuclein, alpha interacting protein [KO:K04558]
7345	UCHL1; ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase) [KO:K05611] [EC:3.4.19.12]
7054	TH; tyrosine hydroxylase [KO:K00501] [EC:1.14.16.2]
6531	SLC6A3; solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 [KO:K05036]
6570	SLC18A1; solute carrier family 18 (vesicular monoamine), member 1 [KO:K08155]
6571	SLC18A2; solute carrier family 18 (vesicular monoamine), member 2 [KO:K08155]
4535	ND1; NADH dehydrogenase, subunit 1 (complex I) [KO:K03878] [EC:1.6.5.3]
4536	ND2; MTND2 [KO:K03879] [EC:1.6.5.3]
4537	ND3; NADH dehydrogenase, subunit 3 (complex I) [KO:K03880] [EC:1.6.5.3]
4538	ND4; NADH dehydrogenase, subunit 4 (complex I) [KO:K03881] [EC:1.6.5.3]
4539	ND4L; NADH dehydrogenase, subunit 4L (complex I) [KO:K03882] [EC:1.6.5.3]
4540	ND5; NADH dehydrogenase, subunit 5 (complex I) [KO:K03883] [EC:1.6.5.3]
4541	ND6; NADH dehydrogenase, subunit 6 (complex I) [KO:K03884] [EC:1.6.5.3]
4723	NDUFV1; NADH dehydrogenase (ubiquinone) flavoprotein 1, 51kDa [KO:K03942] [EC:1.6.99.3 1.6.5.3]
4729	NDUFV2; NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa [KO:K03943] [EC:1.6.99.3 1.6.5.3]
4731	NDUFV3; NADH dehydrogenase (ubiquinone) flavoprotein 3, 10kDa [KO:K03944] [EC:1.6.99.3 1.6.5.3]
4694	NDUFA1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa [KO:K03945] [EC:1.6.99.3 1.6.5.3]
4695	NDUFA2; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa [KO:K03946] [EC:1.6.99.3 1.6.5.3]
4696	NDUFA3; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kDa [KO:K03947] [EC:1.6.99.3 1.6.5.3]
4697	NDUFA4; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kDa [KO:K03948] [EC:1.6.99.3 1.6.5.3]
56901	NDUFA4L2; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 [KO:K03948] [EC:1.6.99.3 1.6.5.3]
4698	NDUFA5; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDa [KO:K03949] [EC:1.6.99.3 1.6.5.3]
4700	NDUFA6; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6, 14kDa [KO:K03950] [EC:1.6.99.3 1.6.5.3]
4701	NDUFA7; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kDa [KO:K03951] [EC:1.6.99.3 1.6.5.3]
4702	NDUFA8; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kDa [KO:K03952] [EC:1.6.99.3 1.6.5.3]
4704	NDUFA9; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa [KO:K03953] [EC:1.6.99.3 1.6.5.3]
4705	NDUFA10; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kDa [KO:K03954] [EC:1.6.99.3 1.6.5.3]
4706	NDUFAB1; NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa [KO:K03955] [EC:1.6.99.3 1.6.5.3]
126328	NDUFA11; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kDa [KO:K03956] [EC:1.6.5.3]
55967	NDUFA12; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12 [KO:K11352] [EC:1.6.99.3 1.6.5.3]
51079	NDUFA13; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13 [KO:K11353] [EC:1.6.99.3 1.6.5.3]
4707	NDUFB1; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa [KO:K03957] [EC:1.6.99.3 1.6.5.3]
4708	NDUFB2; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa [KO:K03958] [EC:1.6.99.3 1.6.5.3]
4709	NDUFB3; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa [KO:K03959] [EC:1.6.99.3 1.6.5.3]
4710	NDUFB4; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa [KO:K03960] [EC:1.6.99.3 1.6.5.3]
4711	NDUFB5; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa [KO:K03961] [EC:1.6.99.3 1.6.5.3]
4712	NDUFB6; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kDa [KO:K03962] [EC:1.6.99.3 1.6.5.3]
4713	NDUFB7; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18kDa [KO:K03963] [EC:1.6.99.3 1.6.5.3]
4714	NDUFB8; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa [KO:K03964] [EC:1.6.99.3 1.6.5.3]
4715	NDUFB9; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa [KO:K03965] [EC:1.6.99.3 1.6.5.3]
4716	NDUFB10; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa [KO:K03966] [EC:1.6.99.3 1.6.5.3]
54539	NDUFB11; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kDa [KO:K11351] [EC:1.6.99.3 1.6.5.3]
4719	NDUFS1; NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75kDa (NADH-coenzyme Q reductase) [KO:K03934] [EC:1.6.99.3 1.6.5.3]
4720	NDUFS2; NADH dehydrogenase (ubiquinone) Fe-S protein 2, 49kDa (NADH-coenzyme Q reductase) [KO:K03935] [EC:1.6.99.3 1.6.5.3]
4722	NDUFS3; NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase) [KO:K03936] [EC:1.6.99.3 1.6.5.3]
4724	NDUFS4; NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase) [KO:K03937] [EC:1.6.99.3 1.6.5.3]
4725	NDUFS5; NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa (NADH-coenzyme Q reductase) [KO:K03938] [EC:1.6.99.3 1.6.5.3]
4726	NDUFS6; NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13kDa (NADH-coenzyme Q reductase) [KO:K03939] [EC:1.6.99.3 1.6.5.3]
374291	NDUFS7; NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase) [KO:K03940] [EC:1.6.99.3 1.6.5.3]
4728	NDUFS8; NADH dehydrogenase (ubiquinone) Fe-S protein 8, 23kDa (NADH-coenzyme Q reductase) [KO:K03941] [EC:1.6.99.3 1.6.5.3]
4717	NDUFC1; NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 1, 6kDa [KO:K03967] [EC:1.6.99.3 1.6.5.3]
4718	NDUFC2; NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa [KO:K03968] [EC:1.6.99.3 1.6.5.3]
100532726	NDUFC2-KCTD14; NDUFC2-KCTD14 readthrough [KO:K03968] [EC:1.6.99.3 1.6.5.3]
6389	SDHA; succinate dehydrogenase complex, subunit A, flavoprotein (Fp) [KO:K00234] [EC:1.3.5.1]
6390	SDHB; succinate dehydrogenase complex, subunit B, iron sulfur (Ip) [KO:K00235] [EC:1.3.5.1]
6391	SDHC; succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa [KO:K00236]
6392	SDHD; succinate dehydrogenase complex, subunit D, integral membrane protein [KO:K00237]
7386	UQCRFS1; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1 [KO:K00411] [EC:1.10.2.2]
4519	CYTB; cytochrome b [KO:K00412]
1537	CYC1; cytochrome c-1 [KO:K00413]
7384	UQCRC1; ubiquinol-cytochrome c reductase core protein I [KO:K00414]
7385	UQCRC2; ubiquinol-cytochrome c reductase core protein II [KO:K00415]
7388	UQCRH; ubiquinol-cytochrome c reductase hinge protein [KO:K00416]
440567	UQCRHL; ubiquinol-cytochrome c reductase hinge protein-like [KO:K00416]
7381	UQCRB; ubiquinol-cytochrome c reductase binding protein [KO:K00417]
27089	UQCRQ; ubiquinol-cytochrome c reductase, complex III subunit VII, 9.5kDa [KO:K00418]
29796	UQCR10; ubiquinol-cytochrome c reductase, complex III subunit X [KO:K00419]
10975	UQCR11; ubiquinol-cytochrome c reductase, complex III subunit XI [KO:K00420]
4514	COX3; cytochrome c oxidase III [KO:K02262]
4512	COX1; cytochrome c oxidase subunit I [KO:K02256] [EC:1.9.3.1]
4513	COX2; cytochrome c oxidase subunit II [KO:K02261]
84701	COX4I2; cytochrome c oxidase subunit IV isoform 2 (lung) [KO:K02263]
1327	COX4I1; cytochrome c oxidase subunit IV isoform 1 [KO:K02263]
9377	COX5A; cytochrome c oxidase subunit Va [KO:K02264]
1329	COX5B; cytochrome c oxidase subunit Vb [KO:K02265]
1337	COX6A1; cytochrome c oxidase subunit VIa polypeptide 1 [KO:K02266]
1339	COX6A2; cytochrome c oxidase subunit VIa polypeptide 2 [KO:K02266]
1340	COX6B1; cytochrome c oxidase subunit VIb polypeptide 1 (ubiquitous) [KO:K02267]
125965	COX6B2; cytochrome c oxidase subunit VIb polypeptide 2 (testis) [KO:K02267]
1345	COX6C; cytochrome c oxidase subunit VIc [KO:K02268]
1346	COX7A1; cytochrome c oxidase subunit VIIa polypeptide 1 (muscle) [KO:K02270]
1347	COX7A2; cytochrome c oxidase subunit VIIa polypeptide 2 (liver) [KO:K02270]
9167	COX7A2L; cytochrome c oxidase subunit VIIa polypeptide 2 like [KO:K02270]
1349	COX7B; cytochrome c oxidase subunit VIIb [KO:K02271]
170712	COX7B2; cytochrome c oxidase subunit VIIb2 [KO:K02271]
1350	COX7C; cytochrome c oxidase subunit VIIc [KO:K02272]
341947	COX8C; cytochrome c oxidase subunit VIIIC [KO:K02273]
1351	COX8A; cytochrome c oxidase subunit VIIIA (ubiquitous) [KO:K02273]
498	ATP5A1; ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1, cardiac muscle [KO:K02132] [EC:3.6.3.14]
506	ATP5B; ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide [KO:K02133] [EC:3.6.3.14]
509	ATP5C1; ATP synthase, H+ transporting, mitochondrial F1 complex, gamma polypeptide 1 [KO:K02136] [EC:3.6.3.14]
513	ATP5D; ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit [KO:K02134] [EC:3.6.3.14]
514	ATP5E; ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit [KO:K02135] [EC:3.6.3.14]
4508	ATP6; ATP synthase F0 subunit 6 [KO:K02126] [EC:3.6.3.14]
515	ATP5F1; ATP synthase, H+ transporting, mitochondrial Fo complex, subunit B1 [KO:K02127] [EC:3.6.3.14]
516	ATP5G1; ATP synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9) [KO:K02128] [EC:3.6.3.14]
517	ATP5G2; ATP synthase, H+ transporting, mitochondrial Fo complex, subunit C2 (subunit 9) [KO:K02128] [EC:3.6.3.14]
518	ATP5G3; ATP synthase, H+ transporting, mitochondrial Fo complex, subunit C3 (subunit 9) [KO:K02128] [EC:3.6.3.14]
10476	ATP5H; ATP synthase, H+ transporting, mitochondrial Fo complex, subunit d [KO:K02138] [EC:3.6.3.14]
539	ATP5O; ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit [KO:K02137] [EC:3.6.3.14]
522	ATP5J; ATP synthase, H+ transporting, mitochondrial Fo complex, subunit F6 [KO:K02131] [EC:3.6.3.14]
4509	ATP8; ATP synthase F0 subunit 8 [KO:K02125] [EC:3.6.3.14]
120892	LRRK2; leucine-rich repeat kinase 2 [KO:K08844] [EC:2.7.11.1]
65018	PINK1; PTEN induced putative kinase 1 [KO:K05688] [EC:2.7.11.1]
11315	PARK7; parkinson protein 7 [KO:K05687]
27429	HTRA2; HtrA serine peptidase 2 [KO:K08669] [EC:3.4.21.108]
7416	VDAC1; voltage-dependent anion channel 1 [KO:K05862]
7417	VDAC2; voltage-dependent anion channel 2 [KO:K15040]
7419	VDAC3; voltage-dependent anion channel 3 [KO:K15041]
291	SLC25A4; solute carrier family 25 (mitochondrial carrier [KO:K05863]
292	SLC25A5; solute carrier family 25 (mitochondrial carrier [KO:K05863]
293	SLC25A6; solute carrier family 25 (mitochondrial carrier [KO:K05863]
83447	SLC25A31; solute carrier family 25 (mitochondrial carrier [KO:K05863]
10105	PPIF; peptidylprolyl isomerase F [KO:K09565] [EC:5.2.1.8]
54205	CYCS; cytochrome c, somatic [KO:K08738]
317	APAF1; apoptotic peptidase activating factor 1 [KO:K02084]
842	CASP9; caspase 9, apoptosis-related cysteine peptidase [KO:K04399] [EC:3.4.22.62]
836	CASP3; caspase 3, apoptosis-related cysteine peptidase [KO:K02187] [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)

KO pathway

ko05012

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Ontology (2)   
   KEGG BRITE (2)   
Pathway (1)   
   BioSystems (1)   
Disease (3)   
   KEGG DISEASE (3)   
Drug (1)   
   KEGG DRUG (1)   
Genome (1)   
   KEGG GENOME (1)   
Gene (131)   
   KEGG GENES (131)   
All databases (139)   

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