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Séminaire - Janelle Drouin-OuelletCan directly induced neurons derived from patients be useful to study sporadic parkinson’s disease?

Abstract :

Directly reprogrammed neurons (induced neurons; iNs) hold great promise for disease modeling of neurodegenerative disorders associated with aging, as they maintain some of the signature associated with age from the parental cells. As such, they could also express the intra-cellular disease related features occurring in idiopathic forms of Parkinson’s disease (PD).  Despite their great promise, reprogramming roadblocks have prevented the generation of iNs at a sufficiently high yield from adult dermal fibroblasts, which has significantly limited the adoption of this technology for biomedical applications. To overcome this, we have developed a new reprogramming protocol to efficiently obtain iNs of high yield and purity from aged individuals, including PD patients.
We next adapted the approach to generate dopaminergic neurons (iDA) to investigate disease-related phenotypes in iDAs derived from sporadic PD patients, with a focus on protein degradation alteration. Our findings suggest a stratification of the sporadic PD cell lines in terms of their response to stress-induced autophagy. Interestingly, some of these impairments are seemingly influenced by factors such as age, disease onset and MAPT genetics, thus perhaps reflecting the clinical heterogeneity of the disease. 

Selected publications

Shrigley S, Pircs K, Barker RA., Parmar M and Drouin-Ouellet J. (2018) Simple generation of a high yield culture of induced neurons from human adult skin fibroblasts. J. Vis. Exp. (132), e56904, doi:10.3791/56904.

Drouin-Ouellet J, Lau S, Brattås PL, Ottosson DR, Pircs K, Grassi DA, Collins LM, Vuono R, Andersson Sjöland A, Westergren-Thorsson G, Graff C, Minthon L., Toresson H, Barker RA, Jakobsson J and Parmar M. (2017) REST suppression mediates neural conversion of adult human fibroblasts via microRNA dependent and independent pathways. EMBO Molecular Medicine, 9(8) :1117-1131. doi: 10.15252/emmm.201607471

Drouin-Ouellet J, Pircs K, Barker RA, Jakobsson J and Parmar M. (2017) Direct neuronal reprogramming for disease modeling studies using patient-derived neurons: What have we learned? Frontiers in Neuroscience; 11 : 530. doi: 10.3389/fnins.2017.00530. eCollection.