Mutations in a P-Type ATPase Gene Cause Axonal Degeneration

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.

Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2

“…Previously, a patient with severe mental retardation and major hypotonia had been reported to carry a de novo balanced translocation of chromosomes 10 and 13 disrupting the coding sequence of the ATP8A2 gene (27). Moreover, wabbler-lethal mice with inactivating deletion or insertion mutations of ATP8A2 have been found to develop severe neurological abnormalities such as ataxia and body tremors, due to distal axonal degeneration in spinal neurons (28).…”

Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival

“…ATP8A2 is a member of the P 4 -ATPase family of phospholipid transporters which is highly expressed in the retina, brain, spinal cord and testis (Cacciagli et al, 2010;Coleman et al, 2009;Zhu et al, 2012). It associates with CDC50A, the b-subunit crucial for the expression and flippase activity of ATP8A2 (Coleman and Molday, 2011;van der Velden et al, 2010).…”

Effect of light on global gene expression in the neuroglobin-deficient mouse retina

“…To the best of our knowledge, we are not aware of any previous studies indicating a functional coupling between Ngb and Entpd4. Atp8a2 is highly expressed in testes, spinal cord, brain and retina (36)(37)(38) and is an adenosine triphosphate (ATP)-dependent lipid flippase that translocates aminophospholipids from the exoplasmic to cytoplasmic leaflets of membranes (39). A straightforward functional association between Atp8a2 and Ngb is unclear as the former is essential for the correct functioning of photoreceptor cells (39), which do not appear to express Ngb (15).…”