Understanding the molecular pathogenesis of GBA1-associated Parkinson's disease by using engineered induced pluripotent stem cells
Final Report Abstract
Parkinson's is the second most common movement disorder that affects around two percent of people over 60 worldwide, and the numbers are rising. Typical symptoms include motor impairments such as unsteady hands, stiff muscles and slow movements. The disease is caused by the loss of dopamine-containing nerve cells in a certain brain region called substantia nigra. There is no effective treatment for this disease to date. Little is known about the causes of the disease. Mitochondrial damage is a key feature in Parkinson's disease. Dopamine neurons, the neurons that are selectively affected in Parkinson's, are particularly susceptible to energy failure. It is not known whether increasing the formation of new young mitochondria and their function is protective in Parkinson's disease. We have found that common gene mutations linked to Parkinson's disease, namely mutations in a gene called GBA, lead to defects in mitochondrial function and the metabolism of nicotinamide adenine dinucleotide (NAD+), which is an essential molecule found in every living cell. Specifically, we show mitochondrial changes in human neurons from Parkinson's disease patients and we demonstrate that the supplementation with a form of vitamin B, nicotinamide riboside, boosts mitochondrial formation and function in Parkinson's disease patient stem cell-derived neurons and it is neuroprotective in Parkinson's disease animal models. Importantly, recent studies have shown that the supplementation with nicotinamide riboside is well tolerated in healthy subjects and efficiently raises NAD+ levels. Thus, we propose that nicotinamide riboside could be a safe and efficacious therapeutic approach in Parkinson's disease patients. https://www.gesundheitsindustrie-bw.de/en/article/news/parkinsons-disease-vitamin-b3-has-a-positive-effect-on-nerve-cells https://uni-tuebingen.de/universitaet/aktuelles-und-publikationen/pressemitteilungen/newsfullview-pressemitteilungen/article/parkinsonvitamin-b3-hat-positive-wirkung-auf-geschaedigte-nervenzellen/
Publications
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Genome editing in pluripotent stem cells: research and therapeutic applications. Biochem Biophys Res Commun. 2016 Feb 27
Deleidi, Michela & Yu, Cong
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"Genome-scale networks link neurodegenerative disease genes to alpha-synuclein through specific molecular pathways". Cell Syst. 2017 Jan 25
Khurana, Vikram; Peng, Jian; Chung, Chee Yeun; Auluck, Pavan K.; Fanning, Saranna; Tardiff, Daniel F.; Bartels, Theresa; Koeva, Martina; Eichhorn, Stephen W.; Benyamini, Hadar; Lou, Yali; Nutter-Upham, Andy; Baru, Valeriya; Freyzon, Yelena; Tuncbag, Nurcan; Costanzo, Michael; San Luis, Bryan-Joseph; Schöndorf, David C.; Barrasa, M. Inmaculada; ... & Lindquist, Susan
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The GBAP1 pseudogene acts as a competing endogenous RNA for the Parkinson-related gene GBA by sponging miR-22-3p. Sci Rep. 2017 Oct 5;7(1):12702
Straniero, Letizia; Rimoldi, Valeria; Samarani, Maura; Goldwurm, Stefano; Di Fonzo, Alessio; Krüger, Rejko; Deleidi, Michela; Aureli, Massimo; Soldà, Giulia; Duga, Stefano & Asselta, Rosanna
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"Nicotinamide riboside rescues mitochondrial defects and neurodegeneration in iPSC and fly models of Parkinson’s disease". Cell Rep. 2018 Jun 5;23(10):2976-2988
Schöndorf, David C.; Ivanyuk, Dina; Baden, Pascale; Sanchez-Martinez, Alvaro; De Cicco, Silvia; Yu, Cong; Giunta, Ivana; Schwarz, Lukas K.; Di Napoli, Gabriele; Panagiotakopoulou, Vasiliki; Nestel, Sigrun; Keatinge, Marcus; Pruszak, Jan; Bandmann, Oliver; Heimrich, Bernd; Gasser, Thomas; Whitworth, Alexander J. & Deleidi, Michela
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"Insights into GBA Parkinson's disease pathology and therapy with induced pluripotent stem cell model systems". Review. Neurobiology of Disease. 2019 Jan 31
Baden, Pascale; Yu, Cong & Deleidi, Michela
