title: Novel interactions of CLN3 protein link Batten disease to dysregulation of fodrin-Na+, K+ ATPase complex.
abstract: Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten disease) is the most common progressive neurodegenerative disorder of childhood. CLN3, the transmembrane protein underlying JNCL, is proposed to participate in multiple cellular events including membrane trafficking and cytoskeletal functions. We demonstrate here that CLN3 interacts with the plasma membrane-associated cytoskeletal and endocytic fodrin and the associated Na(+), K(+) ATPase. The ion pumping activity of Na(+), K(+) ATPase was unchanged in Cln3(-/-) mouse primary neurons. However, the immunostaining pattern of fodrin appeared abnormal in JNCL fibroblasts and Cln3(-/-) mouse brains suggesting disturbances in the fodrin cytoskeleton. Furthermore, the basal subcellular distribution as well as ouabain-induced endocytosis of neuron-specific Na(+), K(+) ATPase were remarkably affected in Cln3(-/-) mouse primary neurons. These data suggest that CLN3 is involved in the regulation of plasma membrane fodrin cytoskeleton and consequently, the plasma membrane association of Na(+), K(+) ATPase. Most of the processes regulated by multifunctional fodrin and Na(+), K(+) ATPase are also affected in JNCL and Cln3-deficiency implicating that dysregulation of fodrin cytoskeleton and non-pumping functions of Na(+), K(+) ATPase may play a role in the neuronal degeneration in JNCL.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute and FIMM, Institute for Molecular Medicine Finland, Biomedicum, PO 104, 00251 Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Uusi-Rauva
authors.forename: Kaisu
authors.initials: K
authors.lastname: Luiro
authors.forename: Kimmo
authors.initials: K
authors.lastname: Tanhuanpää
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Pablo
authors.initials: P
authors.lastname: Martín-Vasallo
authors.forename: Aija
authors.initials: A
authors.lastname: Kyttälä
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007477:Ions / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013049:Spectrin
chemical_list: D000255:Adenosine Triphosphate; D002352:Carrier Proteins; D007477:Ions; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D000254:Sodium-Potassium-Exchanging ATPase; D013049:Spectrin; C105199:CLN3 protein, human