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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/104260
Using pacient-specific IPSC derived dopaminergic to investigate Parkinson's disease: a new prospective in stem cell research and application = Utilització de neurones dopaminèrgiques específiques de pacients derivades de cèl·lules pluripotents induïdes (IPSC) en la investigació de la malaltia de Parkinson: una nova perspectiva en la investigació amb cèl·lules mare i les seves aplicacions
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[eng] Parkinson’s disease (PD) is an incurable neurodegenerative disorder, mainly characterized by a progressive loss of midbrain dopaminergic (DA) neurons, located in the substantia nigra pars compacta (SNpc), and frequently accompanied by the formation of insoluble cytosolic protein aggregates in the remaining surviving neurons, known as Lewy bodies. The progressive denervation of DA terminals that project to the basal ganglia striatum causes a lack of DA uptaking, and consequently a progressive manifestation of debilitating motor deficits, that leads to premature invalidity and death. To date, only symptomatic therapies can compensate efficiently the locomotor deficiencies over a period of 5 years, however they do not cure or halt disease progression. A lack of suitable animal and cellular models might explain the fragmentary knowledge of the pathogenic mechanisms leading to PD, and highlights the urgent need for developing reliable experimental models that can recapitulate the key features of this disorder. The utilization of induced pluripotent stem cells (iPSC) offers an unprecedented opportunity to model human diseases, since they can be generated from patients and differentiated into disease-relevant cell types, such as neurons. Recently, human iPSC-based models of PD have been described. iPSC-derived neurons from patients with familial and sporadic PD recapitulate human disease phenotypes in vitro such as abnormal α-synuclein accumulation, and alterations in the autophagy machinery. Here, we investigated the neuroprotective effect of several compounds, including the neurotrophic factor GDNF, in culture of iPSC-derived midbrain dopaminergic neurons from patients with a LRKK2 mutation or sporadic patients. Interestingly, we found that six weeks after GDNF treatment, the level of dendritic arborisation from DA neurons derived from ID-PD and LRRK2-PD-iPSC increased to normal levels found in Ctrl-iPSC derived DA neurons. The neuroprotective effects were associated to a decrease in the number of apoptotic cells, and to a GFR1α/RET downstream activation of cell survival pathways, as well as reduction of autophagosome vesicles, compared to the untreated PD-iPSC derived DA neurons. Additionally, we found that GDNF is, in part, a requirement for a properly systemic neuronal survival in this model, since levels of GDNF were found twice decreased within long-term DAn cultures derived from both ID-PD and LRRK2-PD, when compared to CTL. In conclusion, our data demonstrate that iPSC-derived neuronal cells are valuable models for measuring responses to neuroprotective therapies and they may help to identify potential new drugs, thus furthering the development of treatments for PD. The differential secretion of survival factors within the culture also highlights the importance of using this technology for studying the contribution of other neural cell types in the onset of PD.
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TORRENT JUAN, Roger. Using pacient-specific IPSC derived dopaminergic to investigate Parkinson's disease: a new prospective in stem cell research and application = Utilització de neurones dopaminèrgiques específiques de pacients derivades de cèl·lules pluripotents induïdes (IPSC) en la investigació de la malaltia de Parkinson: una nova perspectiva en la investigació amb cèl·lules mare i les seves aplicacions. [consulta: 10 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/104260]