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《2012全国发育生物学大会摘要集》2012年
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Mutations in a P-type ATPase gene cause axonal degeneration

Richard T.Libby  Wilhelmine N.de Vries  Richard S.Smith  Dana L.Wright  Roderick T.Bronson  Kevin L.Seburn  Simon W.M.John  
【摘要】:正Neuronal loss and axonal degeneration are important pathological features of many neurodegenerative diseases. The molecular mechanisms underlying the majority of axonal degeneration conditions remain unknown.To better understand axonal degeneration,we studied a mouse mutant wabbler-Iethal(wl).Wabbler-lethal(wl) mutant mice develop progressive ataxia with pronounced neurodegeneration in the central and peripheral nervous system.Previous studies have led to a debate of whether myelinopathy or axonopathy is the primary cause of neurodegeneration observed in wl mice. Here we provide clear evidence that wabbler lethal mutants develop an axonopathy,and that this axonopathy is modulated by Wld and Bax mutations.In addition,we have identified the gene harboring the disease-causing mutations as Atp8a2.We studied three wl alleles and found that all result from mutations in the Atp8a2 gene.Our analysis shows that ATP8A2 possesses phosphatidylserine translocase activity and is involved in localization of phosphatidylserine to the inner leaflet of the plasma membrane.Atp8a2 is widely expressed in the brain,the spinal cord,and retina.We assessed two of the mutant alleles of Atp8a2 and found they are both nonfunctional for the phosphatidylserine translocase activity. Conclusions:Our data demonstrate for the first time that mutation of a mammalian phosphatidylserine translocase causes axon degeneration and neurodegenerative disease.

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