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

Abstract

ATP8A2 is a P 4 -ATPase that is highly expressed in the retina, brain, spinal cord and testes. In the retina, ATP8A2 is localized in photoreceptors where it uses ATP to transport phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the exoplasmic to the cytoplasmic leaflet of membranes. Although mutations in ATP8A2 have been reported to cause mental retardation in humans and degeneration of spinal motor neurons in mice, the role of ATP8A2 in sensory systems has not been investigated. We have analyzed the retina and cochlea of ATP8A2-deficient mice to determine the role of ATP8A2 in visual and auditory systems. ATP8A2-deficient mice have shortened photoreceptor outer segments, a reduction in photoresponses and decreased photoreceptor viability. The ultrastructure and phagocytosis of the photoreceptor outer segment appeared normal, but the PS and PE compositions were altered and the rhodopsin content was decreased. The auditory brainstem response threshold was significantly higher and degeneration of spiral ganglion cells was apparent. Our studies indicate that ATP8A2 plays a crucial role in photoreceptor and spiral ganglion cell function and survival by maintaining phospholipid composition and contributing to vesicle trafficking.

Phosphatidylserine in the brain: Metabolism and function

“…Mutations in the Atp8a2 gene, which is expressed in the brain, spinal cord and retina, inactivates the P-type ATPase ATP8A2. Mutations in Atp8a2 in the mouse cause axonal degeneration, decreased photoreceptor response and viability, and degeneration of spiral ganglion cells [91,92]. …”

Lipid flippase modulates olfactory receptor expression and odorant sensitivity in Drosophila

“…Defects in ATP8B1 expression cause progressive familial intrahepatic cholestasis type 1 (12,17). Lesions in ATP8A1 are associated with abnormalities in the developing nervous system (12,16,(18)(19)(20). Sixteen P4-type ATPases are encoded in the human genome, and six are present in the Drosophila genome, but the function of the majority of these proteins is unknown.…”

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).…”

“…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). As Atp8a2 consumes a notable amount of cellular ATP in the photoreceptor cells (37), it could be hypothesized that if Ngb is involved in oxygen delivery in the retina then a lack of Ngb may lead to a reduced capacity for oxidative phosphorylation resulting in a lower rate for Atp8a2 expression.…”

“…As Atp8a2 consumes a notable amount of cellular ATP in the photoreceptor cells (37), it could be hypothesized that if Ngb is involved in oxygen delivery in the retina then a lack of Ngb may lead to a reduced capacity for oxidative phosphorylation resulting in a lower rate for Atp8a2 expression. Of note, Atp8a2 deficiency leads to the decline in visual perception and auditory failure (39).…”