KEGG   DISEASE: H00057Help
Entry
H00057                      Disease                                

Name
Parkinson's disease (PD)
Description
Parkinson's 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.
Category
Neurodegenerative disease
BRITE hierarchy
Pathway
Parkinson's disease
Gene
(PARK1/PARK4) SNCA (mutation/duplication, triplication) [HSA:6622] [KO:K04528]
(PARK2) Parkin (mutation, genomic rearrangement) [HSA:5071] [KO:K04556]
(PARK5) UCHL1 (mutation) [HSA:7345] [KO:K05611]
(PARK6) PINK1 (mutation) [HSA:65018] [KO:K05688]
(PARK7) DJ1 (mutation) [HSA:11315] [KO:K05687]
(PARK8) LRRK2 (mutation) [HSA:120892] [KO:K08844]
(PARK9) ATP13A2 (mutation) [HSA:23400] [KO:K13526]
(PARK11) GIGYF2 (mutation) [HSA:26058]
(PARK13) HTRA2 (mutation) [HSA:27429] [KO:K08669]
(PARK14) PLA2G6 (mutation) [HSA:8398] [KO:K16343]
(PARK15) FBXO7 (mutation) [HSA:25793] [KO:K10293]
NR4A2 (mutation) [HSA:4929] [KO:K08558]
Env factor
MPTP [CPD:C04599]
Rotenone [CPD:C07593]
Maneb [CPD:C15231]
Paraquat [CPD:C14701]
Marker
Dopamine [CPD:C03758]
Homovanillic acid [CPD:C05582]
Tyrosine hydroxylase [HSA:7054]
DOPA decarboxylase [HSA:1644]
Drug
Carbidopa [DR:D00558] DOPA decarboxylase inhibitor
Levodopa [DR:D00059] dopamine precursor
Biperiden [DR:D00779]
Amantadine hydrochloride [DR:D00777]
Istradefylline [DR:D04641] adenosine A2a receptor antagonist
Comment
Disease class: synucleinopathy
Affected region: substantia nigra, putamen, caudate nucleus, hypothalamus
Microscopic lesion: Lewy bodies
Other DBs
Reference
PMID:19729209 (Env_factor)
  Authors
Cicchetti F, Drouin-Ouellet J, Gross RE
  Title
Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?
  Journal
Trends Pharmacol Sci 30:475-83 (2009)
Reference
  Authors
Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C
  Title
The genetics of Parkinson's syndromes: a critical review.
  Journal
Curr Opin Genet Dev 19:254-65 (2009)
Reference
  Authors
Lesage S, Brice A
  Title
Parkinson's disease: from monogenic forms to genetic susceptibility factors.
  Journal
Hum Mol Genet 18:R48-59 (2009)
Reference
PMID:19182805 (PARK9)
  Authors
Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S
  Title
Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.
  Journal
Nat Genet 41:308-15 (2009)
Reference
PMID:17582365 (PARK2, PARK6, PARK8)
  Authors
Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE
  Title
Deciphering the role of heterozygous mutations in genes associated with parkinsonism.
  Journal
Lancet Neurol 6:652-62 (2007)
Reference
PMID:17499497 (PARK2, PARK6, PARK7)
  Authors
Dodson MW, Guo M
  Title
Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease.
  Journal
Curr Opin Neurobiol 17:331-7 (2007)
Reference
  Authors
Hague SM, Klaffke S, Bandmann O.
  Title
Neurodegenerative disorders: Parkinson's disease and Huntington's disease.
  Journal
J Neurol Neurosurg Psychiatry 76:1058-63 (2005)
Reference
  Authors
Pardo LM, van Duijn CM.
  Title
In search of genes involved in neurodegenerative disorders.
  Journal
Mutat Res 592:89-101 (2005)
Reference
  Authors
Eriksen JL, Przedborski S, Petrucelli L
  Title
Gene dosage and pathogenesis of Parkinson's disease.
  Journal
Trends Mol Med 11:91-6 (2005)
Reference
PMID:15390068 (PARK2)
  Authors
Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, Meija-Santana H, Vieregge P, Jacobs H, Bressman SB, Lang AE, Kann M, Abbruzzese G, Martinelli P, Schwinger E, Ozelius LJ, Pramstaller PP, Klein C, Kramer P
  Title
Distribution, type, and origin of Parkin mutations: review and case studies.
  Journal
Mov Disord 19:1146-57 (2004)
Reference
  Authors
Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW
  Title
The role of pathogenic DJ-1 mutations in Parkinson's disease.
  Journal
Ann Neurol 54:283-6 (2003)
Reference
PMID:12496759 (NR4A2)
  Authors
Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK
  Title
Mutations in NR4A2 associated with familial Parkinson disease.
  Journal
Nat Genet 33:85-9 (2003)

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