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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 the  leucine-rich repeat kinase 2  ( LRRK2 ) gene are a common genetic cause of familial and sporadic PD. However, studies on  LRRK2  mutant mice revealed no visible dopaminergic neuronal loss in the midbrain. While surveying a  LRRK2  knockout mouse strain, we found that old animals developed age-dependent hepatic vascular growths similar to cavernous hemangiomas. In livers of these hemangioma-positive  LRRK2  knockout mice, we detected an increased expression of the HIF-2 α  protein and significant reactivation of the expression of the HIF-2 α  target gene  erythropoietin  ( EPO ), a finding consistent with a role of the HIF-2 α  pathway in blood vessel vascularization. We also found that the kidney  EPO  expression was reduced to 20% of the wild-type level in 18-month-old  LRRK2  knockout 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 kidney  EPO  expression. Our findings reveal a novel function of  LRRK2  in regulating  EPO  expression and imply a potentially novel relationship between PD genes and hematopoiesis.

Altered Expression ofEPOMight Underlie Hepatic Hemangiomas inLRRK2Knockout Mice