title: Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging.
abstract: An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease.
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Neuner
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Garfinkel
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Wilmott
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Bogna M
authors.initials: BM
authors.lastname: Ignatowska-Jankowska
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Ami
authors.initials: A
authors.lastname: Citri
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Orly
authors.affiliation: Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: CRTD-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Rupert W
authors.initials: RW
authors.lastname: Overall
authors.affiliation: Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Mulligan
authors.affiliation: CRTD-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden 01307, Germany; German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden 01307, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Kempermann
authors.affiliation: Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Kristen M S
authors.initials: KM
authors.lastname: O'Connell
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: ckaczoro@uthsc.edu.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Kaczorowski
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D000066492:Cognitive Aging / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D005239:Fear; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics* / Q000523:psychology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology*
chemical_list: C000598191:HP1BP3 protein, mouse; D009687:Nuclear Proteins
keywords: BXD; Cognitive aging; Fear conditioning; Gene set enrichment analysis; Systems genetics