Investigating Glial Contributions During Parkinson’s Disease Pathogenesis Using Patient-Specific iPSC-Derived Cells
[eng] Parkinson’s disease (PD) is associated with the degeneration of ventral midbrain dopaminergic (vmDA) neurons and the accumulation of cytoplasmic inclusions, known as Lewy Bodies, composed mainly of aggregated α synuclein in the surviving vmDA neurons. This process, along with the underlying ce...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/120944 |
| Acceso en línea: | https://hdl.handle.net/2445/120944 http://hdl.handle.net/10803/462955 |
| Access Level: | acceso abierto |
| Palabra clave: | Malaltia de Parkinson Malalties neurodegeneratives Cèl·lules mare Neuròglia Parkinson's disease Neurodegenerative Diseases Stem cells Neuroglia |
| Sumario: | [eng] Parkinson’s disease (PD) is associated with the degeneration of ventral midbrain dopaminergic (vmDA) neurons and the accumulation of cytoplasmic inclusions, known as Lewy Bodies, composed mainly of aggregated α synuclein in the surviving vmDA neurons. This process, along with the underlying cell-autonomous pathogenic mechanisms, has been successfully modeled using patient-specific induced pluripotent stem cell (iPSC) technology. Non-cell autonomous neurodegeneration during PD has been suggested by past observational studies, but remains to be experimentally tested. Here, we generated astrocytes from iPSC lines derived from familial Parkinson’s disease patients with the G2019S mutation on the Leucine rich repeat kinase 2 (LRRK2) gene, and astrocytes from Sporadic PD patients, as well as healthy age-matched individuals (to whom we will refer as wild type (WT)). To assess the possible non-cell autonomous role during PD pathogenesis, a co-culture system was devised between iPSC-derived astrocytes and vmDAn to assess the potential pathogenic neuron-glia crosstalk. WT vmDAn displayed morphological signs of neurodegeneration (such as few and short neurites, as well as beaded-like necklace neurites) and abnormal, astrocyte-derived, α synuclein accumulation when co-cultured on top of LRRK2-PD astrocytes. Upon further investigation, PD astrocytes alone displayed phenotypes reminiscent of those observed in PD-iPSC-derived vmDAn, those including alterations in autophagy and mitochondrial dynamics, as well as a progressive accumulation of α synuclein, when compared with WT astrocytes. A CMA activator drug, QX77.1, successfully rescued CMA dysfunction and as a consequence cleared the previously accumulated α-synucein in PD astrocytes. Conversely, the co-culture of LRRK2-PD vmDA neurons with WT astrocytes partially prevented the appearance of disease- related neurodegeneration. This neuroprotective role appears to be managed via the activation of glia to a reactive state, and suggests LRRK2-PD astrocytes have an impaired relation between neuroprotection and reactivity, which results in neurodamaging effects. Our findings unveil a crucial non-cell autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross-talk between neurons and glial cells. |
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