title: Prolongation of Chemically-Induced Methemoglobinemia in Mice Lacking α-synuclein: A Novel Pharmacologic and Toxicologic Phenotype.
abstract: The proteinα-synuclein is considered central to the pathogenesis of Parkinson disease (PD) on genetic and histopathological grounds. It is widely expressed in fetal life and continues to be highly expressed in adult neural tissues, red blood cells and platelets, while the remainder of adult tissues are reported to have little or no expression. Despite cellular and molecular evidence for a role in neuronal function including synaptic vesicle trafficking, neurotransmitter release, mitochondrial function, lipid metabolism, neurogenesis, neuroprotection, and neuromelanin biosynthesis, mice ablated for the gene encodingα-synuclein (Snca) have little or no neurological phenotype. Thus, nearly 20 years of intensive study have yet to reveal conclusively what the normal function of this highly abundant protein is in the nervous system. Interestingly,α-synuclein has also been shown to have enzymatic activity as a ferrireductase capable of reducing Fe+3to Fe+2. Given its abundant expression in red blood cells, we set out to explore the role ofα-synuclein in converting chemically-induced Fe+3methemoglobin to normal Fe+2hemoglobin. Initialin vivoexperiments with the potent methemoglobin inducer, para-aminopropiophenone and its active metabolite, 4-hydroxy para-aminopropiophenone, demonstrated significantly greater and more prolonged methemoglobinemia inSnca-/- mice compared toSnca+/+ mice.In vitroexperiments with red blood cells, however, and in vivo experiments in genetically engineered mouse strains that differ in theirα-synuclein expression in various tissues, including the nervous system, red blood cells and liver, revealed that contrary to the initial hypothesis, a lack of expression ofα-synuclein in red blood cells did not correlate with higher levels or more prolonged duration of methemoglobinemia. Instead, the greater sensitivity to chemically induced methemoglobinemia correlated with the absence of hepaticα-synuclein expression. We have uncovered a new and robust whole-animal phenotype in mice lackingα-synuclein that reflects its hitherto unrecognized role in xenobiotic detoxification.
authors: Department of Medicine, University of California San Francisco ; Institute for Human Genetics, University of California San Francisco.
authors: Yien-Ming
authors: YM
authors: Kuo
authors: Department of Medicine, University of California San Francisco ; Institute for Human Genetics, University of California San Francisco ; Department of Neurology, University of California San Francisco ; Department of Pathology, University of California San Francisco ; Department of Pediatrics, University of California San Francisco.
authors: Robert L
authors: RL
authors: Nussbaum
keywords: Alpha-Synuclein; Hydroxylamine; Methemoglobin; Para-aminopropiophenone; Parkinson disease