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Results 1-9 of 9.
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   The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson’s DiseaseMencke, Pauline  ; Boussaad, Ibrahim ; Romano, Chiara et alin Cells (2021) Detailed reference viewed: 107 (6 UL) Integrated, automated maintenance, expansion and differentiation of 2D and 3D patient-derived cellular models for high throughput drug screeningBoussaad, Ibrahim ; Cruciani, Gérald ; Bolognin, Silvia et alin Scientific Reports (2021) Detailed reference viewed: 118 (3 UL)PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons; Boussaad, Ibrahim ; Jarazo, Javier et alin Scientific Reports (2021) Detailed reference viewed: 91 (4 UL)GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton 2021.03.04.433895; ; et al E-print/Working paper (2021) Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase ... [more ▼] Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 in a redoxdependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. Changes in the actin cytoskeleton also disrupt mitochondria-ER contact sites. This results in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, these findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology. [less ▲] Detailed reference viewed: 28 (2 UL)Parkinson’s disease phenotypes in patient neuronal cultures and brain organoids improved by 2-Hydroxypropyl-b-Cyclodextrin treatmentJarazo, Javier ; Barmpa, Kyriaki ; et alin Movement Disorders (2021) Detailed reference viewed: 81 (17 UL)Bidirectional Relation Between Parkinson’s Disease and Glioblastoma MultiformeMencke, Pauline ; ; Boussaad, Ibrahim et alin Frontiers in Neurology (2020) Detailed reference viewed: 65 (1 UL)A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.Boussaad, Ibrahim ; ; et alin Science translational medicine (2020), 12(560), Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic ... [more ▼] Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD. [less ▲] Detailed reference viewed: 183 (13 UL)Quality Control Strategy for CRISPRCas9- based Gene Editing Complicated by a PseudogeneHanss, Zoé ; Boussaad, Ibrahim ; Jarazo, Javier et alin Frontiers in Genetics (2019) Detailed reference viewed: 130 (27 UL)Derivation of Human Midbrain-Specific Organoids from Neuroepithelial Stem CellsMonzel, Anna Sophia ; Smits, Lisa ; Hemmer, Kathrin et alin Stem Cell Reports (2017) Detailed reference viewed: 631 (52 UL) |
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