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.

Neurodegenerative disease

nt06410  Calcium signaling
nt06412  Unfolded protein response (UPR) signaling
nt06414  Apoptosis
nt06418  Oxidative phosphorylation
nt06419  Microtubule-based transport
nt06420  Ubiquitin-proteasome system
nt06421  Mitophagy
nt06422  Dopamine metabolism
nt06440  Transcription
nt06463  Parkinson disease

(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] [KO:K18730]
(PARK13) HTRA2 (mutation) [HSA:27429] [KO:K08669]
(PARK14) PLA2G6 (mutation) [HSA:8398] [KO:K16343]
(PARK15) FBXO7 (mutation) [HSA:25793] [KO:K10293]
(PARK17) VPS35 (mutation) [HSA:55737] [KO:K18468]
(PARK18) EIF4G1 (mutation) [HSA:1981] [KO:K03260]
(PARK19) DNAJC16 (mutation) [HSA:23341] [KO:K09536]
(PARK22) CHCHD2 (mutation) [HSA:51142] [KO:K22758]
NR4A2 (mutation) [HSA:4929] [KO:K08558]

MPTP [CPD:C04599]
Rotenone [CPD:C07593]
Maneb [CPD:C15231]
Paraquat [CPD:C14701]

Droxidopa [DR:D01277]
Bromocriptine mesylate [DR:D00780]
Apomorphine hydrochloride [DR:D02004]
Levodopa [DR:D00059]
Carbidopa hydrate and levodopa [DR:D00253]
Carbidopa, levodopa and entacapone [DR:D10293]
Amantadine hydrochloride [DR:D00777]
Ropinirole hydrochloride [DR:D00784]
Pramipexole dihydrochloride [DR:D00559]
Rotigotine [DR:D05768]
Selegiline hydrochloride [DR:D00785]
Rasagiline mesylate [DR:D02562]
Safinamide mesylate [DR:D10191]
Tolcapone [DR:D00786]
Entacapone [DR:D00781]
Opicapone [DR:D10825]
Istradefylline [DR:D04641]
Pimavanserin tartrate [DR:D08969]
Carbidopa [DR:D00558]

Disease class: synucleinopathy
Affected region: substantia nigra, putamen, caudate nucleus, hypothalamus
Microscopic lesion: Lewy bodies

PMID:19729209 (Env_factor)

Cicchetti F, Drouin-Ouellet J, Gross RE

Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?

Trends Pharmacol Sci 30:475-83 (2009)
DOI:10.1016/j.tips.2009.06.005

PMID:19419854

Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C

The genetics of Parkinson's syndromes: a critical review.

Curr Opin Genet Dev 19:254-65 (2009)
DOI:10.1016/j.gde.2009.03.008

PMID:19297401

Lesage S, Brice A

Parkinson's disease: from monogenic forms to genetic susceptibility factors.

Hum Mol Genet 18:R48-59 (2009)
DOI:10.1093/hmg/ddp012

PMID:19182805 (PARK9)

Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S

Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.

Nat Genet 41:308-15 (2009)
DOI:10.1038/ng.300

PMID:17582365 (PARK2, PARK6, PARK8)

Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE

Deciphering the role of heterozygous mutations in genes associated with parkinsonism.

Lancet Neurol 6:652-62 (2007)
DOI:10.1016/S1474-4422(07)70174-6

PMID:17499497 (PARK2, PARK6, PARK7)

Dodson MW, Guo M

Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease.

Curr Opin Neurobiol 17:331-7 (2007)
DOI:10.1016/j.conb.2007.04.010

PMID:16024878

Hague SM, Klaffke S, Bandmann O.

Neurodegenerative disorders: Parkinson's disease and Huntington's disease.

J Neurol Neurosurg Psychiatry 76:1058-63 (2005)
DOI:10.1136/jnnp.2004.060186

PMID:16009383

Pardo LM, van Duijn CM.

In search of genes involved in neurodegenerative disorders.

Mutat Res 592:89-101 (2005)
DOI:10.1016/j.mrfmmm.2005.06.006

PMID:15760766

Eriksen JL, Przedborski S, Petrucelli L

Gene dosage and pathogenesis of Parkinson's disease.

Trends Mol Med 11:91-6 (2005)
DOI:10.1016/j.molmed.2005.01.001

PMID:15390068 (PARK2)

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

Distribution, type, and origin of Parkin mutations: review and case studies.

Mov Disord 19:1146-57 (2004)
DOI:10.1002/mds.20234

PMID:12953260

Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW

The role of pathogenic DJ-1 mutations in Parkinson's disease.

Ann Neurol 54:283-6 (2003)
DOI:10.1002/ana.10675

PMID:12496759 (NR4A2)

Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK

Mutations in NR4A2 associated with familial Parkinson disease.

Nat Genet 33:85-9 (2003)
DOI:10.1038/ng1066

PMID:27090875 (PARK17, PARK18, PARK19)

Hernandez DG, Reed X, Singleton AB

Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

J Neurochem 139 Suppl 1:59-74 (2016)
DOI:10.1111/jnc.13593

PMID:25662902 (PARK22)

Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.

Lancet Neurol 14:274-82 (2015)
DOI:10.1016/S1474-4422(14)70266-2