title: Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects.
abstract: Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Mertens
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Apuã C M
authors.initials: ACM
authors.lastname: Paquola
authors.affiliation: Next Generation Sequencing Core, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Manching
authors.initials: M
authors.lastname: Ku
authors.affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Hatch
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Böhnke
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Shauheen
authors.initials: S
authors.lastname: Ladjevardi
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: McGrath
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Campbell
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Herdy
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: J Tiago
authors.initials: JT
authors.lastname: Gonçalves
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Toda
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yongsung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Hetzer
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: gage@salk.edu.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D002467:Cell Nucleus / Q000378:metabolism*; D002469:Cell Separation; D065150:Cellular Reprogramming; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D059467:Transcriptome; D055815:Young Adult; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D019006:Neural Cell Adhesion Molecules; C417257:RanGTP-binding protein 17; D020931:ran GTP-Binding Protein