The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis

MARCOS, A; CORRADI, G; MAZZITELLI, L; CASALI, CECILIA IRENE; FERNANDEZ , MARIA DEL CARMEN; ADAMO, H; DE TEZANOS PINTO, F

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2019

0005-2736

Mutations in the ATP13A2 gene (PARK9, CLN12, OMIM 610513) wereinitially associated with a form of Parkinson's Disease (PD) known asKufor Rakeb Syndrome (KRS). However, the genetic spectrum of ATP13A2-associated disorders was expanded in the last years, because it has beenfound to underlay variants of neuronal ceroid-lipofuscinoses (NCLs) andhereditary spastic paraplegia. As ATP13A2 seems to be a key component ofthe endo-lysosome pathway, the fact that these pathologies are commonlycharacterized by endo-lysosomal dysfunction is not surprising.Here we report that increasing the level of functional ATP13A2 in astable SH-SY5Y cell line disrupts lipid homeostasis. ATP13A2overexpression increases the fluorescence intensity of the fluorescentanalog phosphatidylethanolamine (NBD-PE) and the formation ofmultilamellar bodies, resembling the so-called "drug-inducedphospholipidosis". We also found that expression of ATP13A2 reduces theceramide-fluorescence intensity and the content ofbis(monoacylglyceryl)phosphate (BMP). BMP is required for lipiddegradation and exosome biogenesis inside acidic compartments, so thisresult suggests that ATP13A2 may be modifying the lipid digestioncapacity and/or the redistribution of lipids in these subcellularorganelles. In addition, ATP13A2-overexpression decreased the totalcontent of triglycerides (TGs), cholesterol and lipid droplets. As TGsare necessary for the synthesis of new membranes, this observationsuggests that increasing the function of ATP13A2 switches the endolysosomal system towards vesicle secretion.