Atp10b-KO Mouse

Atp10b, a P4-type ATPase gene, encodes a late endo -/lysosomal lipid flippase. It transports phosphatidylcholine (PC) and glucosylceramide (GluCer) from the lysosomal exoplasmic to cytoplasmic membrane leaflet, which is crucial for maintaining lipid homeostasis within cells. Dysfunction in this process may impact related cellular pathways, potentially affecting overall cell function and viability [2].

Mutated Atp10B has been associated with an increased risk of Parkinson's disease (PD) [2]. Recessive loss-of-function mutations in Atp10B lead to impaired lysosomal export of GluCer and PC, causing general lysosomal dysfunction and cell death in isolated cortical neurons, thus increasing PD risk [2]. In addition, transient co-expression of Atp10B with its subunit CDC50A stimulates the uptake of fluorescently labeled PC in HeLa cells, and this uptake is specific for PC and dependent on Atp10B's transport function, being impaired by disease-associated variants. The uptake is only increased under specific cell stress conditions, such as treatment with rotenone [1].

In conclusion, Atp10b is essential for endo -/lysosomal lipid flipping and lipid uptake under stress conditions. The study of Atp10b, especially through understanding its loss-of-function effects, has revealed its significance in Parkinson's disease, highlighting its potential as a therapeutic target for this neurodegenerative disorder.

References:

1. Wouters, Rosanne, Beletchi, Igor, Van den Haute, Chris, Eggermont, Jan, Vangheluwe, Peter. 2023. The lipid flippase ATP10B enables cellular lipid uptake under stress conditions. In Biochimica et biophysica acta. Molecular cell research, 1871, 119652. doi:10.1016/j.bbamcr.2023.119652. https://pubmed.ncbi.nlm.nih.gov/38086447/

2. Martin, Shaun, Smolders, Stefanie, Van den Haute, Chris, Vangheluwe, Peter, Van Broeckhoven, Christine. 2020. Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export. In Acta neuropathologica, 139, 1001-1024. doi:10.1007/s00401-020-02145-7. https://pubmed.ncbi.nlm.nih.gov/32172343/