title: Human iPSC-based modeling of late-onset disease via progerin-induced aging.
abstract: Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.
authors: The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Gerstner Sloan-Kettering Graduate School, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.
authors: Justine D
authors: JD
authors: Miller
authors: Yosif M
authors: YM
authors: Ganat
authors: Sarah
authors: S
authors: Kishinevsky
authors: Robert L
authors: RL
authors: Bowman
authors: Becky
authors: B
authors: Liu
authors: Edmund Y
authors: EY
authors: Tu
authors: Pankaj K
authors: PK
authors: Mandal
authors: Elsa
authors: E
authors: Vera
authors: Jae-won
authors: JW
authors: Shim
authors: Sonja
authors: S
authors: Kriks
authors: Tony
authors: T
authors: Taldone
authors: Noemi
authors: N
authors: Fusaki
authors: Mark J
authors: MJ
authors: Tomishima
authors: Dimitri
authors: D
authors: Krainc
authors: Teresa A
authors: TA
authors: Milner
authors: Derrick J
authors: DJ
authors: Rossi
authors: Lorenz
authors: L
authors: Studer
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D002648:Child; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology / Q000637:transplantation / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D034904:Lamin Type A; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism*; D014019:Tissue Donors
chemical_list: D015415:Biomarkers; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A