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• Parkinson's disease societies worldwide
• Ongoing clinical trails, worldwide, can be interrogated at ClinicalTrials.Gov a service of the US National Institutes of Health
• Parkinson's disease genes at PDGene
• pdONLINE RESEARCH ...... Parkinson's disease gene expression database
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• Kegg pathways traced out by Parkinson's disease genes .
• Updates to this page  

Genes that have been associated with Parkinson's disease RSS feeds link to Pubmed

GWAS from Genome.gov

AAK1 ACMSD ATF6 BMP4 BRDG1 BST1 C10orf32 C17orf69 ISM1 (c20orf82) CCDC62 CNNM2 CYP17A1 DBC1 DGKQ DLG2 DSG3 EIF4G1 GAK GBA HIP1R HLA-DRB5 IMP5 ITGA8 KIAA1267 LAMP3 LOC644246 MAPT MCCC1 MMRN1 NSF NUCKS1 OCA2 PARK16 PLEKHM1 PM20D1 PRRG4 QSER1 RAB7L1 RAI1 RIT2 SCARB2 SEMA5A SLC41A1 SNCA SREBF1 STBD1 STK39 SYT11 SYT4 TAS1R2 UNC13B USP25 WNT3

Pre GWAS and others: Data from various sources including Pubmed alerts A B and : PDGene developed by the Max Planck Institute for molecular genetics, Berlin; The Michael J Fox foundation , and the Alzheimer Research forum See also The Genetic Association database at NIH ... Genotator at Harvard University and HUGE navigator See also PDBase The Parkinson Disease Mutation Database Leiden Open Variation Database ..Mutation database for Parkinson's disease

• Major:EIF4G1 LRRK2 PARK2 PARK7 PINK1 SNCA VPS35 SGK1
• Dopamine ADH1C..ADH4 CYP2E1 COMT DBH DRD2 DRD3..MAOB EN1 LMX1A LMX1B NURR1 = NR4A2 PITX3 SLC6A3 Serotonin SLC6A4 NMDA and glutamate DLG2 GLUD2 GRIN1 GRIN2A GRIN2B Oxidative stress CP ..EPHX1 GSTM1 GSTO1 GSTO2..GSTT1 GSTP1 .HFE HMOX1 HMOX2 HP MTHFR NFE2L2 NOS1 NOS2A NQO1 NQO2 PON1 SOD2 TF Mitochondrial ATP13A2 CYTB HSPA9 MTIF3 .ND1.ND2 .ND3 NDUFV2 SIRT5 MtDNA Calcium CAST Immune BST1 CD14 .CLU .HLA-DRA . HLA-DQA2 IL1A IL1B .IL6 .IL8 TNF Autophagy PLEKHM1 Lipoprotein APOE A2M LRP8 Growth BDNF BMP4 FGF20 IGF2 Metabolic DGKQ GBA GCH1 Structural FARP1 MAPT Vitamin B6 / Vitamin D PDXK CALB1 VDR Ubiquitin UCHL1 USP24 USP40 Magnesium SLC41A1 Kinase signalling GAK NUCKS1 MPTP metaboliser CYP2D6 Other xenobiotic related ABCB1 ..CYP1A1 CYP1A2 .CYP17A1. NAT2 (MDR1 + pesticides) Urate SLC2A9 Protease related .HTRA2 SERPINA3 Miscellany ACE ACMSD AKT1 ANG ASCL1..CARD15 CCDC62 CCK DBC1 DLST DMT1 EIF2B3 ..ESR2 .ELAVL4 .FRAXE GIGYF2 GLA . GLIS1 GSK3B HIP1R .HIVEP3 .HNMT .HSPA1 .LAMP3 .LINGO1 LINGO2 . MASH1 MCCC1 MTH1 MTX1 NEDD9 NSF PARK16 PARP1 . PASD1 PHACTR2 . PLA2G6 PM20D1 POLG1 PPARGC1A PRNP..PTGS2 RAB7L1 SEMA5A SLCO3A1 SLC25A48 SLC45A3 SNCB SPP1 .STK39 SYT11 TAS1R2 TOR1A UNC13B VCP . WNT3 LOC644246 KIAA1267 C10orf32 C17orf69 C20orf82 LOC100505836

Copy number variations

• DOCK5 USP

Parkinson's epistasis

MicroRNA's implicated in Parkinson's disease

• MIR1 MIR22 MIR29 miR-16-2, miR-26a2 miR30a Margis et al, 2011
• MIR34B MIR34C Miñones-Moyano et al, 2011
• MIR133B de Mena et al, 2010

• Encephalitis Lethargica possibly related to the 1918 flu pandemic Treatment of these patients with L-DOPA, recorded in the film Awakenings helped to revolutionise Parkinson's disease therapy Foley 2009
• Influenza infection has been related to Substantia nigra cell loss in Man Mihara et al, 2001
• Influenza H1N1 infection in mice targets the Substantia nigra and kills dopamine neurones Jang et al, 2009
  • The influenza virus has been recorded in the substantia nigra of Parkinson's disease brains Rohn and Catlin, 2011
• The Epstein-Barr virus can cause post-encephalitic Parkinsonism Espay and Henderson, 2011
• CSF antibodies to coronavirus have been observed in some patients Fazzini et al, 1992
• Post-mortem brain viral DNA
  • HSV-1: Control 25%: PD 17.5% .
  • HHV-6: Control 87.5% PD 75%
  • Varicella: Control 27.5% PD 40% Hemling et al, 2003
• Serum and CSF antibodies: Herpes simplex virus 1 , measles, and rubella antibody titres were lower in sera of PD patients: Serum influenza antibody titres were higher in post-encephalitic Parkinsonism Elizan et al, 1979
• Association with Japanese B encephalitis virus Das et al, 2011
• The incidence of Parkinson's disease, as well as that of many other disorders has been reported to be increased in poliomyelitis survivors Kang and Lin, 2011
• No association with Arbovirus antibodies Elizan et al, 1978
• A possible association with Toxoplasma Gondii has been reported in Turkey Miman et al, 2010
• An increased incidence of Parkinson's disease has been observed following a whooping cough epidemic (Bordetella pertussis) de Pedro-Cuesta et al, 1996
• Nocardia asteroides infects many old people and has been implicated in Parkinson's disease Kohbata et al, 1993. Infection with this bacterium in mice kills Substantia nigra neurones Tam et al, 2002
• formyl-methionyl-leucyl-phenylalanine , also a bacterial product kills dopamine neurones Gao et al, 2008
• Helicobacter pylori seropositivity has been associated with Parkinson's disease Charlett et al, 1999
  • H.Pylori eradication can improve Parkinsonian symptoms Dobs et al, 2010
  • H.Pylori infection in mice causes locomotor deficits and dopamine depletion Salvatore et al, 2011
• Increased dental loss associated with increased cariogenic bacteria Einarsdóttir et al, 2009
  • Abnormal oral colonisation by gram-negative bacteria (Escherichia coli , Klebsiella, Kluyvera , Serratia , Proteus and Enterobacter species) Gosney et al, 2003
• Increased Staphylococcus aureus in conjunctival flora Kusbeci et al, 2009
• A case of Parkinson's disease secondary to neurosyphilis Spitz et al, 2008
• Reduced risk associated with childhood viral infection particularly measles Sasco et al, 1985
• Increased antibody response to Herpes simplex in Parkinson's disease patients Martilla and Rinne, 1981
• Case report of Parkinsonism produced by gram-negative sepsis Alasia et al, 2006
• Case report of Parkinsonism associated with cryptococcal abscesses of the basal ganglia Camargos et al, 2006
• Parkinsonism asociated with streptococcal infection McKee and Sussman, 2005
• A mild form of acute Parkinson's disease has been observed after a wasp sting Leopold et al, 1999
• Chronic polysystemic candidiasis produces acetaldehyde, which upon reaction with dopamine can produce the neurotoxin Salsalinol Epp and Mravec 2006

• MPTP causes Parkinsonism Langston et al, 1983
• Paraquat and rotenone have been implicated as environmental toxins MPTP, Rotenone and paraquat all block the mitochondrial respiratory chain, although there are differences in precise mechanismsArif and Khan, 2010
  • The effects of paraquat on dopaminergic neurones in mice are attenuated by intergeron gamma ( IFNG ) knockout Mangano et al, 2011 , as are those of MPTP : IFNG also kills dopamine neurones, but only in the presence of microglia Mount et al 2007
• Lipopolysaccharide intracerebral injection causes Parkinsonism like effects and dopaminergic damage in rodents Castaño et al, 1998 (LPSis a component of many bacteria)
• Ammonium chloride and tunicamycin kill dopamine neurones (in fish) Matsui et al, 2010
• Exposure to pesticides has been associated with Parkinson's disease Hatcher et al, 2008
• B4GALNT1 (beta-1,4-N-acetyl-galactosaminyl transferase 1 )knockdown produces parkinsonism in mice (synthesises ganglosides) Kegg pathway .Wu et al, 2011
• Elevated serum levels of the organochlorine pesticide ß-hexachlorocyclohexane have been reported in Parkinsonian patients Richardson et al, 2011
• Trichloroethylene inhibits mitochondrial respiration and has been implicated in Parkinson's disease Gash et al, 2008
• Pesticides and Parkinson's disease database
• TEMPEST : A Task Exposure Matrix for Pesticides : Various studies
• The consumption of whalemeat and blubber (probably a concentration of food chain toxins) has been linked to Parkinson's disease: beta-hexachlorocyclohexane was also linked to increased risk Petersen et al, 2008
• BMAA ( beta-Methylamino-L-alanine ), a toxin derived from Cycad seeds causes a degenerative disease with Parkinsonian features in Guam Vyas and Weiss, 2009 . BMAA can also be produced by cyanobacteria Cox et al, 2003
• Methamphetamine use has been implicated as a risk factor Callaghan et al, 2010
• A metabolite from S. venezuelae kills dopaminergic neurones in nematodes and in mammalian SH-SY5Y cells Caldwell et al, 2009
• Organophosphates have been linked to Parkinson's disease Das et al, 2011

Metals and Parkinson's disease

• Previous exposure to manganese has been associated with increased risk Park et al, 2005
• Urban Parkinson disease incidence is higher in US counties with high industrial release of copper or manganese Willis et al, 2010
• A significant correlation between blood manganese and signal intensity in T1-weighted MRI images has been reported in liver-disease patients with Parkinson-like signs Hudnell, 1999
• Cumulative lead exposure has been associated with Parkinson's disease Weisskopf et al, 2010
• Significantly lower levels of Cobalt, Chromium, Iron, Lead, Silicon and Tin were observed in the CSF of PD patients compared with those in controls, with a percentage depletion of up to 50% for Chromium and Lead Alimonti et al, 2007.
• Decreased Aluminium , Sulphur, Iron and zinc plasma concentrations: Increased potassium, Magnesium and Copper concentrations Hegde et al, 2004
• Aluminium, copper, iron, manganese and zinc abnormalities contribute to risk Ahmed and Santosh 2010
• Occupational exposure to mercury increases the risk of hospital admissions for neurological, Parkinson's or renal diseases Thygesen et al, 2011

• Early exposure to a rural environment associated with increased risk (see pesticides)Rajput et al, 1987
• Working in agriculture, hunting, and forestry has been associated with increased risk Park et al, 2005
• Parkinson's disease patients tend to have had fewer domestic animals at home during their lifetime, including cows, sheep, pigs, and chickens Kuopio et al, 1999.
• Dietary vegetables, lutein, xanthophylls, xanthins, carbohydrates, monosaccharides, junk food, refined sugar, lactose, animal fat, total fat, nuts and seeds, tea, Iron, and total energy associated with increased risk: Ishihara and Brayne, 2005
• Dietary fish, egg, potatoes, bread, alcohol, coffee, tea, niacin, pantothenic acid, folate and pyridoxine associated with reduced risk Ishihara and Braine,2005 See also Skeie et al, 2010
  • The coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of CYP1A2 polymorphisms Popat et al, 2011.
• Dietary patterns with a high intake of fruit, vegetables, legumes, whole grains, nuts, fish, and poultry and a low intake of saturated fat and a moderate intake of alcohol may protect against Parkinson's disease.Gao et al,1997
• Higher dietary intake of vitamin B6 was associated with a significantly decreased risk of Parkinson's disease, in smokers De Lau et al, 2006
• Living near rubber plants and drinking river water asociated with increased risk in China Wang et al, 1993
• An inverse association with cigarette smoking has been observedHernan et al, 2001
• Tobacco chewing protected and hypertension increased Parkinson's disease incidence in an Indian study Das et al, 2010.
• Moderate caffeine intake may have a protective effect Ascherio et al, 2001
• Hormone replacement therapy has little effect but may modify the effects of caffeine and smoking Simon et al, 2009
• Black tea consumption inversely associated with Parkinson's disease in China Tan et al, 2008
• Non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDS) may have a beneficial effect Ghang and Power, 2010 Aspirin and salicylate also block the neurotoxic effects of MPTP Aubin et al, 1998
• Ibuprofen may reduce the risk of developing Parkinson's disease Gao et al, 2011
• Inverse association between the intakes of beta-carotene or ascorbic acid and Parkinson's disease Sepcic et al, 1993
• Parkinson's disease risk is reduced in men working outdoors (possible relationship with Vitamin D and sunlight) Kenborg et al, 2010
• Well water drinking as well as exposure to insecticides and pesticides has been associated with Parkinson's disease Das et al, 2011
• Hypnotic, anxiolytic or antidepressant drug use for more than 1 year has been associated with Parkinson's disease Dick et al, 2007
• Under-nutrition is a problem for around 15% of community dwelling people with Parkinson's disease Jaafar et al, 2010

Biochemistry

• Loss of dopamine neurones in the basal ganglia (substantia nigra) Hornykiewicz 1962
• Glutathione levels are reduced in the substantia nigra in Parkinson.s disease Sian et al, 1994
• Lipid peroxidation is increased in the substantia nigra Dexter et al, 1986
• Low plasma levels of octopamine in early stages D'Andrea et al, 2010
• Increased plama levels of taurine in early stages Vitreshchak et al, 2004
• Vitamin D deficiency has been associated with Parkinson's disease Evatt et al, 2008 and vitamin D may be protective Knekt et al, 2010
• Elevated levels of homocysteine and methylmalonate in serum and urine Levin et al, 2010
• Plasma urate has been associated with a lower risk of Parkinson's disease in men but not in women O'Reilly et al, 2010
• High haemoglobin levels have been associated with Parkinson'sdisease in older men Abbott et al, 2010
• Mitochondrial complex V activity is reduced in Parkinson's disease fibroblasts Del Hoyo et al, 2010
• Increased plasma levels of malondialdehyde (related to oxidative stress) Sanyal et al, 2010
• Increased plasma levels of 8-hydroxy-2-deoxyguanosine, a marker of oxidative DNA damage, with decreased uric acid and increased glutathione levels Bogdanov et al, 2008
• Increased plasma levels of DJ-1 Waragai et al, 2007
• Increased erythrocyte and brain levels of oxidised DJ-1 Akazawa et al, 2010
• Decreased plasma levels of alpha-synuclein Li et al, 2007
• Increased serum levels of hepatocyte growth factor Salehi and Rajaei, 2010
• Antibodies to melanin have been observed in Parkinson's disease Double at al, 2009
• Antibodies to dopamine have been noted Mankovskii et al, 1993
• Antibodies to TNF and interferon gamma have been noted in Parkinson's disease Gribova et al, 2003
• Antibodies to alpha synuclein have been observed in familial Parkinson's disease Papachroni et al, 2007
• Antibodies to insulin and S100B have been noted in Parkinson's disease Wilhelm et al, 2007
• Antibodies to substantia nigra neurones have been noted Chen et al, 2001
• Anti GM1 ganglioside antibodies have been noted Zappia et al, 2002
• HSP65 and HSP70 antibodies have been noted in Parkinson's disease CSF Fiszer at al, 1996
• Antibodies against the latent membrane protein 1 of the Epstein-Barr virus label Lewy bodies and cross-react with alpha-synuclein Woulfe et al, 2000
• Lewy body constituents: ACO2 AP2A1 AP2B1 ATIC ATP6V1A CADPS CBR1 CLTC COPA CUL1 DCLK1 DCTN1 DNM1L DPYSL2 DYNC1H1 FBXO2 GAPDH GNAO1 GPI GSN HSPA8 HSP90AB1 MAP2K1 OTUB1 PDIA3 PLEC PRDX5 PRKCB PSMD2 RNF123 S100A9 SNCA SPTAN1 SPTBN1 UBA1 UBA52 UCHL1 VPS35 WDR1 XIA et al 2008 Leverens et el, 2007 and many more , see papers

Comorbidity and others

• Repetitive head trauma (eg boxing dementia pugilistica ) may increase the risk of developing Parkinson's diseases Lolekha et al, 2010
• Parkinson's disease is associated with decreasing darkness of hair colour Gao et al, 2009
• Osteoporosis is common in Parkinson's disease, particularly with insufficient sun exposure and low calcium intake uric acid and gout DeVera et al, 2008
• Inverse associations of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of Parkinson's disease in Japan Miyake et al, 2010
• High total baseline cholesterol is associated with increased risk (Finland) Hu et al, 2008
• Dietary glycaemic index negatively correlated with Parkinson's disease Murakami et al, 2010
• Inverse association with diabetes D'Amelio et al, 2009
• An inverse association with height Ragonese et al, 2007
• However, in older patients who has diabetes for more that 10 years the risk of later developing Parkinson's disease was higher Xu et al, 2011
• Working in a service occupation negatively associated with PD riskKirke et al, 2001
• Higher early adult physical exercise is associated with reduced risk Chen et al, 2005
• An inverse association between Tumours and Parkinson's disease D'Amelio et al, 2004
• But an increased incidence of melanoma and skin carcinoma prior to developing Parkinson's disease Olsen et al, 2006
• In young women, endometriosis slightly increases the risk of Parkinson's disease Latourelle et al, 2010
• Several inflammatory diseases, including rheumatism, cystitis, and acute pancreatitis are associated with an increased risk of developing Parkinson's disease : Latourelle et al, 2010 This paper, by examining many estrogen related disorders, concluded that oestrogen may be a protective factor in Parkinson's disease
• Previous general anaesthesia asoociated with increased riskZorzon et al, 2002
• Parkinson's disease is less frequent in Afro-Americans Yakoubiam et al, 2009 and rare in Bulgarian Gypsys Mylanov et al, 2000
• Parkinson's disease prevalence is slightly higher in those born in spring as opposed to winter and is also linked to maternal age Gardener et al, 2010
• Many patients have sleep disorders: frequent awakening, excessive daytime sleepiness, nightmares, nocturnal cramps and REM sleep behavior disorders Hasegawa, 2004 .
• Associated with restless legs syndrome Verbaan et al, 2010

Pesticides and Parkinson’s Disease an open access book chapter

The worldwide distribution of Parkinson's disease: from Wikipedia and Lokal_profil

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