Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer’s disease

Kaneshiro, Nanaka; Komai, Masato; Imaoka, Ryosuke; Ikeda, Atsuya; Kamikubo, Yuji; Saito, Takashi; Saido, Takaomi C.; Tomita, Taisuke; Hashimoto, Tadafumi; Iwatsubo, Takeshi; Sakurai, Takashi; Uehara, Takashi; Takasugi, Nobumasa

doi:10.1016/j.isci.2022.103869

Cited by 9 publications

(9 citation statements)

References 49 publications

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“…In addition, some members localize to the ER, endosomes and/or lyso somes. Although the involvement of the lipid transporters in the various events, such as endocytic recycling, endocytosis, exocytosis and fission of organelles, has been proposed 29,[243][244][245] , it is not well understood whether the proteins in the scramblase and flippase families have an instructive role in these processes and how exactly they impact these membrane dynamics events. This is because, compared with the proteins in plasma membranes, more difficulties are associated with examining the biological activity of these proteins in specific organelles using a cell-based assay system.…”

Section: Review Articlementioning

confidence: 99%

Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Sakuragi

Nagata

2023

Nat Rev Mol Cell Biol

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Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed o f g ly ce ro ph os ph olipids, sphingolipids and cholesterol, in which proteins are embedded. G l y ce r o ph o s ph olipids and sphingolipids freely move laterally, whereas t r a ns v e rse m o v em ent between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins -flippases and scramblases -mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases. SectionsThe role of P4-type ATPases in lipid 'flipping' between the bilayer. P-type ATPases constitute a large protein family that transport cations and lipids across the membrane 24 . They are named 'P-type' because a conserved aspartic acid is transiently modified by phosphorylation during the reaction cycle. A phylogenic analysis divided the family into five subfamilies (P1-P5 types). Similar to other P-type ATPases, P4-ATPases are membrane proteins with cytoplasmic amino c Caspase-mediated PtdSer exposure Apoptotic bodies

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Section: Review Articlementioning

confidence: 99%

Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Sakuragi

Nagata

2023

Nat Rev Mol Cell Biol

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“…In addition, TMEM30A is essential for insulin maturation and secretion, lymphomagenesis, and skeletal muscle regeneration [ 31 – 33 ]. This molecule has been identified as a potential therapeutic target for endosomal anomalies in Alzheimer’s disease [ 34 ]. Hearing onset in mice occurs at postnatal days 12–14.…”

Section: Discussionmentioning

confidence: 99%

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

Xing

Peng

et al. 2023

Cell Mol Biol Lett

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Background Phosphatidylserine is translocated to the inner leaflet of the phospholipid bilayer membrane by the flippase function of type IV P-tape ATPase (P4-ATPase), which is critical to maintain cellular stability and homeostasis. Transmembrane protein 30A (TMEM30A) is the β-subunit of P4-ATPase. Loss of P4-ATPase function causes sensorineural hearing loss and visual dysfunction in human. However, the function of TMEM30A in the auditory system is unclear. Methods P4-ATPase subtype expression in the cochlea was detected by immunofluorescence staining and quantitative real-time polymerase chain reaction (qRT-PCR) at different developmental stages. Hair cell specific TMEM30A knockout mice and wild-type littermates were used for the following functional and morphological analysis. Auditory function was evaluated by auditory brainstem response. We investigated hair cell and stereocilia morphological changes by immunofluorescence staining. Scanning electron microscopy was applied to observe the stereocilia ultrastructure. Differentially expressed transcriptomes were analyzed based on RNA-sequencing data from knockout and wild-type mouse cochleae. Differentially expressed genes were verified by qRT-PCR. Results TMEM30A and subtypes of P4-ATPase are expressed in the mouse cochlea in a temporal-dependent pattern. Deletion of TMEM30A in hair cells impaired hearing onset due to progressive hair cell loss. The disrupted kinocilia placement and irregular distribution of spectrin-α in cuticular plate indicated the hair cell planar polarity disruption in TMEM30A deletion hair cells. Hair cell degeneration begins at P7 and finishes around P14. Transcriptional analysis indicates that the focal adhesion pathway and stereocilium tip-related genes changed dramatically. Without the TMEM30A chaperone, excessive ATP8A2 accumulated in the cytoplasm, leading to overwhelming endoplasmic reticulum stress, which eventually contributed to hair cell death. Conclusions Deletion of TMEM30A led to disrupted planar polarity and stereocilia bundles, and finally led to hair cell loss and auditory dysfunction. TMEM30A is essential for hair cell polarity maintenance and membrane homeostasis. Our study highlights a pivotal role of TMEM30A in the postnatal development of hair cells and reveals the possible mechanisms underlying P4-ATPase-related genetic hearing loss.

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“…A laboratory in 2018 showed that TMEM30A was a candidate partner for β -carboxyl terminal fragments ( β CTF) of amyloid- β precursor protein (APP), which physically interacted with β CTF in endosomes, impairing vesicle trafficking, resulting in abnormal enlargement of endosomes and impaired APP flow, and leading to the accumulation of APP-CTF, including β CTF [ 41 ]. They further reported in 2022 that the interaction between TMEM30A and β CTF was one of the important pathogenesis of Alzheimer's disease [ 20 ], which inhibited the physiological complex formation and activity of lipid flippase in SH-BACE1 cells, and the BACE1 inhibitor treatment recovered this interaction. In AD model mice, A7 and App NL − G-F/NL − G-F knock-in model mice, they found TMEM30A/ β CTF complex formation and subsequent lipid flippase dysfunction preceded A β deposition.…”

Section: Nervous Systemmentioning

confidence: 99%

“…However, the subcellular localization of the complex is determined by P4-ATPase rather than TMEM30A [ 18 ]. Some researchers indicated that TMEM30A may transport short-chain choline phospholipids into mammalian cells [ 19 ] and regulate the trafficking of amyloid- β precursor protein (APP) in endosomes [ 20 , 21 ]. It is also worth noting that TMEM30A is suggested as the potential receptor for SARS-CoV-2 cell entry, but the mechanism needs further study [ 14 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Physiological and Pathological Functions of TMEM30A: An Essential Subunit of P4-ATPase Phospholipid Flippases

Zhao²,

Wang

2023

Journal of Lipids

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Phospholipids are asymmetrically distributed across mammalian plasma membrane. The function of P4-ATPases is to maintain the abundance of phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the inner leaflet as lipid flippases. Transmembrane protein 30A (TMEM30A, also named CDC50A), as an essential β subunit of most P4-ATPases, facilitates their transport and functions. With TMEM30A knockout mice or cell lines, it is found that the loss of TMEM30A has huge influences on the survival of mice and cells because of PS exposure-triggered apoptosis signaling. TMEM30A is a promising target for drug discovery due to its significant roles in various systems and diseases. In this review, we summarize the functions of TMEM30A in different systems, present current understanding of the protein structures and mechanisms of TMEM30A-P4-ATPase complexes, and discuss how these fundamental aspects of TMEM30A may be applied to disease treatment.

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Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer’s disease

Cited by 9 publications

References 49 publications

Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

Physiological and Pathological Functions of TMEM30A: An Essential Subunit of P4-ATPase Phospholipid Flippases

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