Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Oct 13

PMID 26456686

Citations 374

Authors

Jerome Mertens

Apua C M Paquola

Manching Ku

Emily Hatch

Lena Bohnke

Shauheen Ladjevardi

Sean McGrath

Benjamin Campbell

Hyungjun Lee

Joseph R Herdy

J Tiago Goncalves

Tomohisa Toda

Yongsung Kim

Jurgen Winkler

Jun Yao

Martin W Hetzer

Fred H Gage

Affiliations

Soon will be listed here.

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.

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