title: Deficiency of the INCL protein Ppt1 results in changes in ectopic F1-ATP synthase and altered cholesterol metabolism.
abstract: Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disease caused by deficiency of palmitoyl protein thioesterase 1 (PPT1). INCL results in dramatic loss of thalamocortical neurons, but the disease mechanism has remained elusive. In the present work we describe the first interaction partner of PPT1, the F(1)-complex of the mitochondrial ATP synthase, by co-purification and in vitro-binding assays. In addition to mitochondria, subunits of F(1)-complex have been reported to localize in the plasma membrane, and to be capable of acting as receptors for various ligands such as apolipoprotein A-1. We verified here the plasma membrane localization of F(1)-subunits on mouse primary neurons and fibroblasts by cell surface biotinylation and TIRF-microscopy. To gain further insight into the Ppt1-mediated properties of the F(1)-complex, we utilized the Ppt1-deficient Ppt1(Delta ex4) mice. While no changes in the mitochondrial function could be detected in the brain of the Ppt1(Delta ex4) mice, the levels of F(1)-subunits alpha and beta on the plasma membrane were specifically increased in the Ppt1(Delta ex4) neurons. Significant changes were also detected in the apolipoprotein A-I uptake by the Ppt1(Delta ex4) neurons and the serum lipid composition in the Ppt1(Delta ex4) mice. These data indicate neuron-specific changes for F(1)-complex in the Ppt1-deficient cells and give clues for a possible link between lipid metabolism and neurodegeneration in INCL.
authors.affiliation: National Public Health Institute and FIMM, Institute for Molecular Medicine, Biomedicum Helsinki, PO Box 104, FIN-00251 Helsinki, Finland.
authors.forename: Annina
authors.initials: A
authors.lastname: Lyly
authors.forename: Sanna K
authors.initials: SK
authors.lastname: Marjavaara
authors.forename: Aija
authors.initials: A
authors.lastname: Kyttälä
authors.forename: Kristiina
authors.initials: K
authors.lastname: Uusi-Rauva
authors.forename: Kaisu
authors.initials: K
authors.lastname: Luiro
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Martinez
authors.forename: Kimmo
authors.initials: K
authors.lastname: Tanhuanpää
authors.forename: Nisse
authors.initials: N
authors.lastname: Kalkkinen
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism; D001921:Brain / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D021122:Protein Subunits / Q000032:analysis / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000032:analysis / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000097:blood / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D008055:Lipids; D021122:Protein Subunits; C478189:respiratory complex II; D002784:Cholesterol; D042963:Electron Transport Complex II; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D006180:Proton-Translocating ATPases