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.

AS-D was partially supported by a pre-doctoral fellowship from MEC. Additional support was provided by grants from MICINN (BFU2009- 13277, PLE2009-0144 and ACI2010-1117 to AR; RyC-2008- 02772 and BFU2010-21823 to AC; SAF2008-04360, to JA; SAF2009-07774 and PLE2009-0089, to JMC), FIS (PI10/00849 to MV; RD06/0010/0006 to JMC), NIH/NIA AG031782/ AG038072 (to AMC) and Fondazione Guido Berlucchi (to AC). The Cell Therapy Program was supported by the CMRB (Promt-0901 to JMC). The work was also part of a CIBERNED Cooperative Project (to JA, JL-B, MV, ET and AR).

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