Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS


PD-HUMMODEL Sintesi della relazione

Project ID: 311736
Finanziato nell'ambito di: FP7-IDEAS-ERC
Paese: Spain

Mid-Term Report Summary - PD-HUMMODEL (Elucidating early pathogenic mechanisms of neurodegeneration in Parkinson's disease through a humanized dynamic in vitro model)

Parkinson’s disease (PD) is an incurable chronically progressive neurodegenerative disease that affects between 8-10 million people worldwide. Despite decades of intense research, the pathogenic mechanisms behind PD are for the most part still unknown, owing to the lack of experimental models that recapitulate the main features of the disease. Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease, since they can be generated from patients and differentiated into disease-relevant cell types, including neurons, which would capture the patients’ genetic complexity. Recently, we developed a human cell-based model for Parkinson’s disease using iPSC from patients suffering sporadic or familial PD, and age-matched controls, which were used to generate patient-specific dopamine neurons (DAn). We found that patients’ DAn show PD-relevant phenotypes such as abnormal α-synuclein accumulation, alterations in the autophagy machinery, and increased susceptibility to undergo neurodegeneration upon long-term culture.
By taking advantage of this genuinely human PD model, the specific objectives of the PD-HUMMODEL project are to investigate:i) the pathogenic mechanisms that underlie the neurodegeneration phenotype identified in our model, with the aim of finding ways to delay, halt or rescue the neurodegeneration of PD patients; ii) early functional alterations in patient-specific iPSC-derived DAn, which would predate neurodegeneration signs and provide valuable information as to ways to prevent, rather than rescue, neurodegeneration in PD patients; iii) further refinements in our iPSC-based PD model, including the generation of iPSC lines representing asymptomatic patients carrying pathogenic mutations, and the correction of known mutations by gene edition, all of which will allow exploring the relationship between pathogenic mutations and the genetic makeup of patients; and iv) whether DAn degeneration in PD is solely a cell-autonomous phenomenon, or whether it is influenced by an altered cross-talk between DAn and glial cells.
During the first 30 months of the PDHUMMODEL project, the milestones proposed for this period have been achieved, and good progress has been made toward the completion of other activities. Specifically, we have identified and characterized the alterations in mitochondrial morphology and dynamics in patients’ DAn compared to controls, and we have extended these studies to iPSC-derived astrocytes as well. We have also begun to assess the synaptic properties of iPSC-derived DAn. Moreover, we have found large-scale aberrations in DNA methylation in DAn from sporadic and familial PD patients, which were not present in the patients’ fibroblasts, undifferentiated iPSC, or in iPSC-derived neurons other than DAn. Finally, we have complemented our PD model with additional iPSC lines derived from asymptomatic patients carrying pathogenic mutations, with iPSC lines from familial PD patients where the mutation has been corrected, and with iPSC lines from healthy individuals where the same mutation has been introduced by gene edition. The availability of this comprehensive collection of iPSC lines and isogenic controls will enable studying the relative contribution of the gene mutation and the complex genetic makeup of patients in PD onset and progression. Overall, our research may not only lead to the discovery of early diagnostic markers, but also enable drug screening for compounds that suppress or prevent some of the neurotoxic processes that occur in PD.

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