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SUMMARY:&quot\;Modeling GBA1-associated Parkinson's disease using patient 
 iPSCs&quot\; - Michela Deleidi\, MD\, Hertie-Institute for Clinical Brain 
 Research\, Department of Neurodegenerative Diseases\, German Center for Ne
 urodegenerative Diseases (DZNE)\, University of Tübingen  
DTSTART:20140324T140000Z
DTEND:20140324T150000Z
UID:TALK51098@talks.cam.ac.uk
CONTACT:Shannon Tinley-Browne
DESCRIPTION:Parkinson's disease (PD) is a progressive neurodegenerative di
 sorder characterized\nby the preferential loss of dopaminergic (DA) neuron
 s in the substantia nigra pars\ncompacta. Several clues key to understandi
 ng disease pathogenesis come from\nmutations in genes which have been link
 ed to inherited forms of PD. Among these\,\nmutations in the acid β-gluco
 cerebrosidase (GBA1) gene\, responsible for the\nlysosomal storage disorde
 r Gaucher’s disease (GD)\, are the strongest genetic risk\nfactor for PD
  known to date. To elucidate the mechanisms underlying\nneurodegeneration 
 in these patients\, we generated induced pluripotent stem cells\n(iPSCs) f
 rom subjects with GD and PD harboring GBA1 mutations as well as\nneurologi
 cally healthy individuals. To control for the influence of the patient gen
 etic\nbackground and perform genotype-phenotype correlations\, we generate
 d isogenic\nGBA1 corrected lines by using zinc finger nuclease (ZFN)-induc
 ed homologous\nrecombination. All iPSC lines were successfully differentia
 ted to midbrain DA\nneurons and enriched by fluorescence-activated cell so
 rting. Importantly\, such\npurified human iPSC-derived neurons mirrored th
 e sphingolipid content of the adult\nhuman brain. Diseased neurons show a 
 reduction of glucocerebrosidase activity and\nprotein levels\, increased g
 lucosylceramide and α-synuclein levels and defects in the\nlysosomal/auto
 phagic machinery. A large-scale quantitative proteomic profile on\npurifie
 d neurons and imaging studies revealed dysregulation of calcium homeostasi
 s\nand increased vulnerability to cellular stress responses involving elev
 ation of\ncytosolic calcium in mutant neurons. Importantly such phenotypes
  were reverted\nupon gene correction\, thus supporting a direct link betwe
 en GBA1 mutations and\nclinical relevant phenotypes. In summary\, our find
 ings provide evidence for a link\nbetween GBA1 mutations and complex chang
 es in the lysosomal function and\nintracellular calcium homeostasis\, whic
 h may underlie vulnerability to\nneurodegeneration.
LOCATION:Brain Repair Centre\, Forvie Site\, Robinson Way
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