Taken together our findings suggest that in PD the

Taken together, our findings suggest that in PD, the heterozygous GBA-N370S mutation leads to the misprocessing of GCase, ER stress upregulation, and autophagic/lysosomal dysfunction in dopaminergic neurons. We propose that this combination of disturbances impairs protein homeostasis in dopamine neurons, which leads to increased α-synuclein release. Such cellular events in combination may lead to preferential dopamine neuronal vulnerability in PD.
Experimental Procedures
Acknowledgments The work was supported by the Monument Trust Discovery Award from Parkinson\'s UK, The Oxford Martin School, which provides core support to the James Martin Stem Cell Facility (LC0910-004) and the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115439, resources of which are composed of financial contribution from the European Union\'s Seventh Framework Program (FP7/2007e2013) and EFPIA companies\' in kind contribution. The work was supported by the Monument Trust Discovery Award from Parkinson\'s UK. The OPDC Discovery cohort was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford, and the Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). H.J.R.F. was supported by a Fundacao para a Ciencia e Tecnologia (FCT) grant (SFRH/BD/65787/2009) and S.C. has been supported by a Wellcome Trust Career Re-Entry Fellowship (WT082260/Z/07/Z). We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics, Oxford (funded by Wellcome Trust grant reference 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of Illumina genotyping and transcriptome data.
Introduction Maturity-onset diabetes of the young (MODY) is a type of autosomal Aminoallyl-dUTP - Cy3 monogenic diabetes classically characterized by non-ketotic, non-insulin-dependent diabetes occurring before the age of 25 years (Teo et al., 2013a). Many MODY genes are pancreatic developmental transcription factors, with the notable exception of GCK, CEL, and INS. Although MODY was discovered more than two decades ago, the molecular mechanisms underlying transcription factor MODY in humans is still largely unclear because mouse models do not fully recapitulate this disease (Maestro et al., 2007) and the lack of a suitable human model. Patients with MODY5 commonly exhibit pancreatic hypoplasia due to an autosomal dominant mutation in the HNF1B gene (Edghill et al., 2006). HNF1B is a member of the complex pancreatic transcription factor network which includes HNF1A and HNF4A. HNF1B+ cells in the pancreatic trunk epithelium are multipotent pancreatic progenitors which play a role in endocrine and exocrine development (Haumaitre et al., 2005). Although MODY5 was discovered in 1997, to date the effects of an autosomal dominant mutation in HN1B on human pancreas development and the molecular mechanisms underlying pancreatic hypoplasia remain not fully understood. MODY5 phenotype in humans cannot be phenocopied by Hnf1β+/− mice since they do not develop diabetes (Haumaitre et al., 2005), highlighting the need for a suitable human model to study the perturbations in pancreas development (Teo et al., 2013a). Human-induced pluripotent stem cell (hiPSC)-derived pancreatic cells now provide an excellent opportunity to study this monogenic diabetes phenotype. In this study, we established a well-controlled MODY5-hiPSC pancreatic differentiation model to elucidate the molecular mechanisms underlying MODY5 pancreatic hypoplasia. We differentiated four control and six mutant hiPSC lines, and observed that mutant HNF1B elicits a compensatory increase in definitive endoderm (DE) and pancreatic transcription factor gene expression. Mutant HNF1B directly accounted for an increased PDX1 gene expression. These pancreatic transcription factor network perturbations could possibly explain the occurrence of maturity-onset diabetes rather than neonatal diabetes despite pancreatic hypoplasia. Importantly, pancreatic PAX6 gene expression, known to be important for pancreatic β-cell function, was distinctly down-regulated in MODY5 pancreatic progenitors, which in part explains the early-onset diabetes and pancreatic hypoplasia in MODY5 patients.