Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.
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.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. ghliu@ibp.ac.cn
Guang-Hui
GH
Liu
Jing
J
Qu
Keiichiro
K
Suzuki
Emmanuel
E
Nivet
Mo
M
Li
Nuria
N
Montserrat
Fei
F
Yi
Xiuling
X
Xu
Sergio
S
Ruiz
Weiqi
W
Zhang
Ulrich
U
Wagner
Audrey
A
Kim
Bing
B
Ren
Ying
Y
Li
April
A
Goebl
Jessica
J
Kim
Rupa Devi
RD
Soligalla
Ilir
I
Dubova
James
J
Thompson
John
J
Yates
Concepcion Rodriguez
CR
Esteban
Ignacio
I
Sancho-Martinez
Juan Carlos
JC
Izpisua Belmonte
D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D009685:Nuclear Envelope / Q000235:genetics / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D013312:Stress, Physiological
D050505:Mutant Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex