Table 1. Gene–environment interactions in Parkinson’s disease.

Environmental risk factors	Genes/products	Protective factors
a,bOld age, a,bestrogen deficiency (in women); Rural living, a,bherbicides, pesticide exposure (paraquat, rotenone, organochlorines, carbamates); bMetal exposure, head injury, a,binfectious diseases during childhood; Maternal factors/early life events b(virus, drugs, endotoxins, hormone deficits); Drug-induced parkinsonism (bdrug abuse, neuroleptics, calcium-channel blockers)	Familial PD PARK1–PARK18 (aPARK2/Parkin, aPARK17/VPS35), a,bLRRK2, α-synuclein, UCH-L1, Tau	cEstrogen replacement therapy (in post-menopausal women and OVX animals); cDietary factors/life style (tea, polyphenols, wine components, curcumin, drinking coffee, tobacco smoking); a,dEnvironment enrichment, exercise and social interactions; a,cChronic use of NSAIDs reduces risk by ~45%
	Dopaminergic DA receptors, DAT, TH, COMT, MAO a,bGSK-3p can contribute to PD risk
	Xenobiotic Metabolism/Detox CYP2D, CYP1A1, NAT, a,bHmox, GST, NQO2
	Lipoprotein Apolipoprotein E
	Survival/neurotrophic factors aNOR1, Nurr1, NGF, BDNF
	a,bInflammatory genes NOS, TNF-α, IL-1β, IL-6, ER-β

DAT, dopamine transporter; TH, tyrosine hydroxylase; COMT, catechol-o-methyl-transferase; MAO, monoamino-oxidase; CYP2D, debrisoquine 4-hydroxylase; CYP1A1, cytochrome P450 1A1; NAT, N-acetyltransferase; Hmox, heme oxygenase 1; GST, glutathione transferase; NQO2, NAD(P)H:quinone oxidoreductase 2; NOR1, orphan nuclear receptor subfamily 4, group A, member 3; Nurr1, orphan nuclear receptor subfamily 4, group A, member 2; NGF, nerve growth factor; BDNF, brain derived neurotrophic factor.

^aWnt/β-catenin dysregulation.

^bActivation of microglia and pro-inflammatory mediators in animal models of PD.

^cMitigation/inhibition of microglial activation in animal models of PD.

^dEnhanced neurogenesis/synaptic plasticity and glial proliferation.