Abstract
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-lethal (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 as to 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 Wlds 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, spinal cord, and retina. We assessed two of the mutant alleles of Atp8a2 and found they are both nonfunctional for the phosphatidylserine translocase activity. Thus, our data demonstrate for the first time that mutation of a mammalian phosphatidylserine translocase causes axon degeneration and neurodegenerative disease.
Highlights
Neuronal loss and axonal degeneration are important pathological features of neurodegenerative diseases, such as Alzheimer disease, Parkinson’s disease, amyotrophic lateral sclerosis and glaucoma
Axon degeneration and axonopathies are often observed in human neurodegenerative diseases, but their molecular causes are typically not known
Together with our finding that the Wallerian degeneration slow (Wlds) mutation, which protects against axon injury, significantly delayed axonal degeneration [25,26,27,28,29,30,36,37,38,39], this provides strong evidence that the wl mutation induces an axonopathy [11,12,13,14,15]
Summary
Neuronal loss and axonal degeneration are important pathological features of neurodegenerative diseases, such as Alzheimer disease, Parkinson’s disease, amyotrophic lateral sclerosis and glaucoma. Axonopathies, conditions in which axon injury occurs first during disease progression, have been extensively studied, but the mechanism(s) underlying axon degeneration remain to be elucidated in most of these conditions. Spontaneous mouse mutants have long been used to gain insight into human disease. Spontaneous mutants provide valuable platforms for identifying disease-associated pathways. Identifying the gene(s) that cause a certain phenotype in mice can lead to a greater understanding of the pathophysiology of a disease. As with all forward genetic tools, the power of analyzing mutants is that it allows for the identification of pathways involved in disease that may not have been identified through experiments based on current knowledge. To understand axon pathophysiology better, we studied wabbler-lethal (wl) mutant mice that display axon degeneration.
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