Human Molecular Genetics Advance Access originally published online on February 1, 2008
Human Molecular Genetics 2008 17(10):1406-1417; doi:10.1093/hmg/ddn028
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Deficiency of the INCL protein Ppt1 results in changes in ectopic F1-ATP synthase and altered cholesterol metabolism
1 National Public Health Institute and FIMM, Institute for Molecular Medicine, Biomedicum Helsinki, PO Box 104, FIN-00251 Helsinki, Finland 2 Research Program of Molecular Neurology 3 Folkhälsan Institute of Genetics and the Neuroscience Center, University of Helsinki, Biomedicum Helsinki, FIN-00014 Helsinki, Finland 4 INSERM, U563, Université Toulouse III Paul Sabatier, IFR30, Toulouse, France 5 Light Microscopy Unit, Institute of Biotechnology, University of Helsinki, PO Box 56, FIN-00014 Helsinki, Finland 6 Protein Chemistry Research Group and Core Facility, Institute of Biotechnology, University of Helsinki, PO Box 65, FIN-00014 Helsinki, Finland
* To whom correspondence should be addressed. Tel: +358 947448392; Fax: +358 947448480; Email: anu.jalanko{at}ktl.fi
Received December 7, 2007; Accepted January 24, 2008
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 F1-complex of the mitochondrial ATP synthase, by co-purification and in vitro-binding assays. In addition to mitochondria, subunits of F1-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 F1-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 F1-complex, we utilized the Ppt1-deficient Ppt1
ex4 mice. While no changes in the mitochondrial function could be detected in the brain of the Ppt1ex4 mice, the levels of F1-subunits 
and β on the plasma membrane were specifically increased in the Ppt1ex4 neurons. Significant changes were also detected in the apolipoprotein A-I uptake by the Ppt1ex4 neurons and the serum lipid composition in the Ppt1ex4 mice. These data indicate neuron-specific changes for F1-complex in the Ppt1-deficient cells and give clues for a possible link between lipid metabolism and neurodegeneration in INCL.