Journal
EMBO MOLECULAR MEDICINE
Volume 4, Issue 5, Pages 380-395Publisher
WILEY
DOI: 10.1002/emmm.201200215
Keywords
autophagy; disease modeling; LRRK2 mutation; neurodegeneration; pluripotent stem cells
Categories
Funding
- MEC
- MICINN [BFU2009-13277, PLE2009-0144, ACI2010-1117, RyC-2008-02772, BFU2010-21823, SAF2008-04360, SAF2009-07774, PLE2009-0089]
- FIS [PI10/00849, RD06/0010/0006]
- NIH/NIA [AG031782/AG038072]
- Fondazione Guido Berlucchi
- CMRB [Promt-0901]
- ICREA Funding Source: Custom
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Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.
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