title: Cellular prion protein directly interacts with and enhances lactate dehydrogenase expression under hypoxic conditions.
abstract: Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clarified, a PrP(c)-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion protein knockout mice (Prnp(0/0)) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrP(c). Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp(0/0) knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line. While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp(0/0) primary cortical neurons with concurrent less hypoxia-induced damage in the former group. Likewise, cerebral ischemia significantly increases LDH levels in WT vs. Prnp(0/0) mice with accompanying smaller lesions in the WT group. HEK293 cells overexpressing PrP(c) show significantly higher LDH expression/activity following 90-min of hypoxia as compared to control cells. Moreover, a cytoplasmic co-localization of LDH and PrP(c) was recorded under both normoxic and hypoxic conditions. Interestingly, an expression of monocarboxylate transporter 1, responsible for cellular lactate uptake, increases with PrP(c)-overexpression under normoxic conditions. Our data suggest LDH as a direct PrP(c) interactor with possible physiological relevance under low oxygen conditions.
authors.affiliation: Pfuetzner Science and Health Institute, 55116 Mainz, Germany; Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.
authors.forename: Sanja
authors.initials: S
authors.lastname: Ramljak
authors.affiliation: Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany. Electronic address: Matthias.Schmitz@med.uni-goettingen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitz
authors.affiliation: Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.
authors.forename: Saima
authors.initials: S
authors.lastname: Zafar
authors.affiliation: Department of Neuropathology, Georg-August University, 37075 Goettingen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Wrede
authors.affiliation: Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Schenkel
authors.affiliation: Department of Clinical Chemistry, Georg-August University, 37075 Goettingen, Germany.
authors.forename: Abdul R
authors.initials: AR
authors.lastname: Asif
authors.affiliation: Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Carimalo
authors.affiliation: Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Department of Neuropathology, Georg-August University, 37075 Goettingen, Germany.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Schulz-Schaeffer
authors.affiliation: Department of Neurology, University of Jena Medical School, 07747 Jena. Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Weise
authors.affiliation: Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases (DZNE) - site Göttingen 37075 Goettingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism
chemical_list: D027501:Monocarboxylic Acid Transporters; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D014404:Tubulin; D007770:L-Lactate Dehydrogenase
keywords: Cellular prion protein; Hypoxia; Lactate dehydrogenase; Monocarboxylate transporter 1; Neuroprotection