title: Altered Expression ofEPOMight Underlie Hepatic Hemangiomas inLRRK2Knockout Mice.
abstract: Parkinson's disease (PD) is a severe neurodegenerative disorder caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The molecular mechanism of PD pathogenesis is unclear. Mutations in theleucine-rich repeat kinase 2(LRRK2) gene are a common genetic cause of familial and sporadic PD. However, studies onLRRK2mutant mice revealed no visible dopaminergic neuronal loss in the midbrain. While surveying aLRRK2knockout mouse strain, we found that old animals developed age-dependent hepatic vascular growths similar to cavernous hemangiomas. In livers of these hemangioma-positiveLRRK2knockout mice, we detected an increased expression of the HIF-2αprotein and significant reactivation of the expression of the HIF-2αtarget geneerythropoietin(EPO), a finding consistent with a role of the HIF-2αpathway in blood vessel vascularization. We also found that the kidneyEPOexpression was reduced to 20% of the wild-type level in 18-month-oldLRRK2knockout mice. Unexpectedly, this reduction was restored to wild-type levels when the knockout mice were 22 months to 23 months old, implying a feedback mechanism regulating kidneyEPOexpression. Our findings reveal a novel function ofLRRK2in regulatingEPOexpression and imply a potentially novel relationship between PD genes and hematopoiesis.
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, No. 110 Xiangya Road, Changsha, Hunan 410078, China.
authors.forename: Ben
authors.identifier: 0000-0002-0861-861X
authors.initials: B
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, No. 110 Xiangya Road, Changsha, Hunan 410078, China.
authors.forename: Kaifu
authors.initials: K
authors.lastname: Xiao
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, No. 110 Xiangya Road, Changsha, Hunan 410078, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, No. 110 Xiangya Road, Changsha, Hunan 410078, China.
authors.forename: Long
authors.identifier: 0000-0002-3925-9154
authors.initials: L
authors.lastname: Ma
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006391:Hemangioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000172:deficiency* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009363:Neoplasm Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C495279:Lrrk2 protein, mouse