Abstract
Parkinson's disease (PD) is a neurodegenerative disorder related to nigrostriatal dopaminergic neuron degeneration and iron accumulation. As a cellular oxygen sensor, prolyl hydroxylase domain containing protein 2 (PHD2, encoded by egl-9 family hypoxia inducible factor 1, EGLN1) modifies hypoxia-inducible factor alpha (HIF-α) protein for proteasomal destruction under normoxic condition. In addition, 2-oxoglutarate- (OG-) dependent dioxygenase activity of PHD2 is involved in the oxygen and iron regulation of iron-responsive element binding protein 2 (IRP2) stability. Previously increased expression of EGLN1 was found in the substantia nigra of the parkinsonian brain. We investigated the possible role of c.380 G > C (p.C127S) of EGLN1 gene in Taiwanese patients with PD. 479 patients and 435 healthy controls were recruited. Polymerase chain reaction and BsmAI restriction enzyme analysis were applied for analysis. An association between CC genotype and reduced PD risk in the recessive model (CC vs. GG + GC) was found. Our study provides a link between EGLN1 c.380 G > C SNP and the development of PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by α-synuclein aggregation in the brain and loss of dopaminergic neurons in the substantia nigra (SN)
The disease etiology remains to be clarified, proteins encoded by PD-causing genes such as SNCA, Parkin, DJ1, PINK1, and LRRK2 are involved in the oxidative stress pathway that contributes to neurodegeneration of PD [1]
Previous study by Grunblatt et al found increased gene expression of EGLN1 in the SN of parkinsonian brains using oligonucleotide microarray technique [3]. e EGLN1 gene encodes proline hydroxylase domain 2 (PHD2), which is an oxygen/ iron sensor that belongs to the 2-oxoglutarate- (2-OG-) dependent dioxygenase superfamily. e upregulation of EGLN1 promotes the degradation of hypoxic-inducible factor (HIF), an iron homeostasis-related protein [4]
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by α-synuclein aggregation in the brain and loss of dopaminergic neurons in the substantia nigra (SN). The disease etiology remains to be clarified, proteins encoded by PD-causing genes such as SNCA, Parkin, DJ1, PINK1, and LRRK2 are involved in the oxidative stress pathway that contributes to neurodegeneration of PD [1]. Among the sources and mechanisms for the generation of oxidative stress, dysfunction of iron homeostasis and iron accumulation in the SN may be involved in the development of PD [2]. Previous study by Grunblatt et al found increased gene expression of EGLN1 (egl-9 family hypoxia inducible factor 1) in the SN of parkinsonian brains using oligonucleotide microarray technique [3]. E EGLN1 gene encodes proline hydroxylase domain 2 (PHD2), which is an oxygen/ iron sensor that belongs to the 2-oxoglutarate- (2-OG-) dependent dioxygenase superfamily. E upregulation of EGLN1 promotes the degradation of hypoxic-inducible factor (HIF), an iron homeostasis-related protein [4]. A high frequency of linked c.[12C > G; 380 G >C] or p.[Asp4Glu; Cys127Ser] variation in Tibetans [8] and Sherpas [9] was found in recent studies, which results in an adaptive function of the EGLN1
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