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Article Dans Une Revue Nature Année : 2012

Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

Guang-Hui Liu
  • Fonction : Auteur
Jing Qu
  • Fonction : Auteur
Keiichiro Suzuki
  • Fonction : Auteur
Mo Li
  • Fonction : Auteur
Nuria Montserrat
  • Fonction : Auteur
Fei Yi
  • Fonction : Auteur
Xiuling Xu
  • Fonction : Auteur
Sergio Ruiz
  • Fonction : Auteur
Audrey Kim
  • Fonction : Auteur
Bing Ren
  • Fonction : Auteur
Ying Li
April Goebl
  • Fonction : Auteur
Jessica Kim
  • Fonction : Auteur
Rupa Devi Soligalla
  • Fonction : Auteur
Ilir Dubova
  • Fonction : Auteur
John Yates
  • Fonction : Auteur
Concepcion Rodriguez Esteban
  • Fonction : Auteur
Ignacio Sancho-Martinez
  • Fonction : Auteur
Juan Carlos Izpisua Belmonte
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-01736204 , version 1 (16-03-2018)

Identifiants

Citer

Guang-Hui Liu, Jing Qu, Keiichiro Suzuki, Emmanuel Nivet, Mo Li, et al.. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature, 2012, 491 (7425), pp.603--607. ⟨10.1038/nature11557⟩. ⟨hal-01736204⟩
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