iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
David C. Schöndorf,Massimo Aureli,Fiona E. McAllister,Christopher J. Hindley,Florian Mayer,Benjamin Schmid,S. Pablo Sardi,Manuela Valsecchi,Susanna A. Hoffmann,Lukas Kristoffer Schwarz,Ulrike Hedrich,Daniela Berg,Lamya S. Shihabuddin,Jing Hu,Jan Pruszak,Steven P. Gygi,Sandro Sonnino,Thomas Gasser,Michela Deleidi +18 more
TL;DR: Induced pluripotent stem cells are generated from subjects with GD and PD harbouring GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration are provided.
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Abstract: Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher's disease (GD), are the strongest genetic risk factor for Parkinson's disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and protein levels, increase in glucosylceramide and α-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.
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Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies.
Kathrin Brockmann,Corinne Quadalti,Stefanie Lerche,Marcello Rossi,Isabel Wurster,Simone Baiardi,Benjamin Roeben,Angela Mammana,Milan Zimmermann,Ann-Kathrin Hauser,Christian Deuschle,Claudia Schulte,Katharina Waniek,Ingolf Lachmann,Simon Sjödin,Ann Brinkmalm,Ann Brinkmalm,Kaj Blennow,Kaj Blennow,Henrik Zetterberg,Thomas Gasser,Piero Parchi +21 more
TL;DR: In this article, a real-time quaking-induced conversion (RT-QuIC) analysis of CSF has been used to detect misfolded α-synuclein (α-Syn) in patients with Parkinson's disease and dementia with Lewy bodies (DLB).
Abnormal hippocampal neurogenesis in Parkinson’s disease: relevance to a new therapeutic target for depression with Parkinson’s disease
TL;DR: A novel framework for targeting adult hippocampal neurogenesis is presented, which could provide a promising treatment for PD-associated depression and review PD- associated pathophysiological factors regulating neuro genesis, including inflammatory signaling and autophagy.
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Opportunities and challenges for the use of induced pluripotent stem cells in modelling neurodegenerative disease.
TL;DR: Recent progress in generating Alzheimer's, Parkinson's and Huntington's disease models from patient-derived iPSCs are reviewed and novel discoveries of pathological mechanisms and drug evaluations that have used these patient iPSC-derived neuronal models are described.
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Gaucher-related synucleinopathies: the examination of sporadic neurodegeneration from a rare (disease) angle.
TL;DR: The link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.
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•Journal Article
Variants associated with Gaucher disease in multiple system atrophy (S7.006)
Jun Mitsui,Takashi Matsukawa,Hidenao Sasaki,Ichiro Yabe,Masaaki Matsushima,Alexandra Durr,Alexis Brice,Hiroshi Takashima,Shoji Tsuji +8 more
TL;DR: To investigate the role of GBA variants in multiple system atrophy (MSA), a large case–control series is analyzed.
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Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease
Ellen Sidransky,Mike A. Nalls,Jan O. Aasly,Judith Aharon-Peretz,Grazia Annesi,Egberto Reis Barbosa,Anat Bar-Shira,Daniela Berg,Jose Bras,Jose Bras,Alexis Brice,Alexis Brice,Chiung-Mei Chen,Lorraine N. Clark,Christel Condroyer,Elvira Valeria De Marco,Alexandra Durr,Alexandra Durr,Michael J. Eblan,Stanley Fahn,Matthew J. Farrer,Hon-Chung Fung,Ziv Gan-Or,Thomas Gasser,Ruth Gershoni-Baruch,Ruth Gershoni-Baruch,Nir Giladi,Nir Giladi,Alida Griffith,Tanya Gurevich,Tanya Gurevich,Cristina Januário,Peter Kropp,Anthony E. Lang,Guey Jen Lee-Chen,Suzanne Lesage,Karen Marder,Ignacio F. Mata,Anat Mirelman,Jun Mitsui,Ikuko Mizuta,Giuseppe Nicoletti,Giuseppe Nicoletti,Catarina R. Oliveira,Ruth Ottman,Avi Orr-Urtreger,Lygia da Veiga Pereira,Aldo Quattrone,Aldo Quattrone,Ekaterina Rogaeva,Arndt Rolfs,Hanna Rosenbaum,Roberto Rozenberg,Ali Samii,Ali Samii,Ali Samii,Ted Samaddar,Claudia Schulte,Manu Sharma,Manu Sharma,Andrew B. Singleton,Andrew B. Singleton,Mariana Spitz,Mariana Spitz,Eng-King Tan,Eng-King Tan,Nahid Tayebi,Tatsushi Toda,André R. Troiano,Shoji Tsuji,Matthias Wittstock,Tyra G. Wolfsberg,Yih-Ru Wu,Cyrus P. Zabetian,Yi Zhao,Shira G. Ziegler +75 more
TL;DR: Data collected demonstrate that there is a strong association between GBA mutations and Parkinson's disease, and those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were morelikely to have atypical clinical manifestations.
Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease
Sonja Kriks,Jae-Won Shim,Jinghua Piao,Yosif Ganat,Dustin R. Wakeman,Zhi-Zhong Xie,Luis Carrillo-Reid,Gordon Auyeung,Chris Antonacci,Amanda Buch,Lichuan Yang,M. Flint Beal,D. James Surmeier,Jeffrey H. Kordower,Viviane Tabar,Lorenz Studer +15 more
TL;DR: A novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo is presented, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells.
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