title: MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging.
abstract: Ependymal cells (ECs) form a barrier responsible for selective movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. Here, we demonstrate that metabolic and barrier functions in ECs decline significantly during aging in mice. The longevity of these functions in part requires the expression of the myristoylated alanine-rich protein kinase C substrate (MARCKS). Both the expression levels and subcellular localization of MARCKS in ECs are markedly transformed during aging. Conditional deletion of MARCKS in ECs induces intracellular accumulation of mucins, elevated oxidative stress, and lipid droplet buildup. These alterations are concomitant with precocious disruption of ependymal barrier function, which results in the elevation of reactive astrocytes, microglia, and macrophages in the interstitial brain tissue of young mutant mice. Interestingly, similar alterations are observed during normal aging in ECs and the forebrain interstitium. Our findings constitute a conceptually new paradigm in the potential role of ECs in the initiation of various conditions and diseases in the aging brain.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Nagendran
authors.initials: N
authors.lastname: Muthusamy
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sommerville
authors.affiliation: Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Moeser
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Durham, NC, 27709, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stumpo
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Sannes
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Adler
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Durham, NC, 27709, USA.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.affiliation: Sanford Research, Children's Health Research and Department of Pediatric, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, 57104, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Weimer
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.|Program in Genetics, North Carolina State University, Raleigh, NC, 27607, USA.
authors.forename: H Troy
authors.initials: HT
authors.lastname: Ghashghaei
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D004805:Ependyma / Q000166:cytology* / Q000378:metabolism*; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D009077:Mucins / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D018384:Oxidative Stress; D016548:Prosencephalon / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D009077:Mucins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate
keywords: Clca3; aging; barrier function; cerebral cortex; ependymal cells; lipid droplets; mucin; oxidative stress