Exosome/microvesicle content is altered in leucine‐rich repeat kinase 2 mutant induced pluripotent stem cell‐derived neural cells. Issue 7 (30th November 2019)

• Record Type: Journal Article
• Authors: Candelario, Kate M.; Balaj, Leonora; Zheng, Tong; Skog, Johan; Scheffler, Bjorn; Breakefield, Xandra; Schüle, Birgitt; Steindler, Dennis A.
• Is Part Of: Journal of comparative neurology. Volume 528:Issue 7(2020)
• Page Start: 1203
• Page End: 1215
• Publication Date: 2019-11-30
• Subjects: extracellular vesicles RRID 000067128 -- Parkinson's disease RRID 010300 -- stem cells RRID 13234; Comparative neurobiology -- Periodicals; Neurology -- Periodicals; 616
• DOI: 10.1002/cne.24819
• Languages: English
• ISSNs: 0021-9967

Abstract

Abstract: Extracellular vesicles, including exosomes/microvesicles (EMVs), have been described as sensitive biomarkers that represent disease states and response to therapies. In light of recent reports of disease‐mirroring EMV molecular signatures, the present study profiled two EMVs from different Parkinson's disease (PD) tissue sources: (a) neural progenitor cells derived from an endogenous adult stem/progenitor cell, called adult human neural progenitor (AHNP) cells, that we found to be pathological when isolated from postmortem PD patients' substantia nigra; and (b) leucine‐rich repeat kinase 2 (LRRK2) gene identified patient induced pluripotent stem cells (iPSCs), which were used to isolate EMVs and begin to characterize their cargoes. Initial characterization of EMVs derived from idiopathic patients (AHNPs) and mutant LRRK2 patients showed differences between both phenotypes and when compared with a sibling control in EMV size and release based on Nanosight analysis. Furthermore, molecular profiling disclosed that neurodegenerative‐related gene pathways altered in PD can be reversed using gene‐editing approaches. In fact, the EMV cargo genes exhibited normal expression patterns after gene editing. This study shows that EMVs have the potential to serve as sensitive biomarkers of disease state in both idiopathic and gene‐identified PD patients and that following gene‐editing, EMVs reflect a corrected state. This is relevant for both prodromal and symptomatic patient populations where potential responses to therapies can be monitored via non‐invasive liquid biopsies and EMV characterizations. Abstract : Induced pluripotent stem cells from a patient with Parkinson's disease, and having the leucine‐rich repeat kinase 2 (LRRK2) G2019S mutation, were differentiated into dopaminergic neurons and their in vitro‐released exosomes/microvesicles (EMVs) analyzed and compared with EMVs from control and gene‐corrected induced pluripotent stem cell‐derived dopaminergic neurons. Gene expression patterns, correlated with neurodegenerative disorders, were differentially expressed in EMVs from LRRK2 mutant cells as compared with controls, and expression was restored to control levels for many of the genes when the mutation was corrected.