Progressive Degeneration of Human Neural Stem Cells Caused by Pathogenic LRRK2

Overview

Journal Nature

Specialty Science

Date 2012 Oct 19

PMID 23075850

Citations 187

Authors

Guang-Hui Liu

Jing Qu

Keiichiro Suzuki

Emmanuel Nivet

Mo Li

Nuria Montserrat

Fei Yi

Xiuling Xu

Sergio Ruiz

Weiqi Zhang

Ulrich Wagner

Audrey Kim

Bing Ren

Ying Li

April Goebl

Jessica Kim

Rupa Devi Soligalla

Ilir Dubova

James Thompson

John Yates 3rd

Concepcion Rodriguez Esteban

Ignacio Sancho-Martinez

Juan Carlos Izpisua Belmonte

Affiliations

Soon will be listed here.

Abstract

Nuclear-architecture defects have been shown to correlate with the manifestation of a number of human diseases as well as ageing. It is therefore plausible that diseases whose manifestations correlate with ageing might be connected to the appearance of nuclear aberrations over time. We decided to evaluate nuclear organization in the context of ageing-associated disorders by focusing on a leucine-rich repeat kinase 2 (LRRK2) dominant mutation (G2019S; glycine-to-serine substitution at amino acid 2019), which is associated with familial and sporadic Parkinson's disease as well as impairment of adult neurogenesis in mice. Here we report on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson's disease patients and the implications of LRRK2(G2019S) mutation in human neural-stem-cell (NSC) populations. Mutant NSCs showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear-envelope organization, clonal expansion and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2(G2019S) mutation with its wild-type counterpart in Parkinson's disease iPSCs and were recapitulated after targeted knock-in of the LRRK2(G2019S) mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear-envelope impairment in clinically diagnosed Parkinson's disease patients. Together, our results identify the nucleus as a previously unknown cellular organelle in Parkinson's disease pathology and may help to open new avenues for Parkinson's disease diagnoses as well as for the potential development of therapeutics targeting this fundamental cell structure.

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