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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #357311
Title: Exosome/microvesicle content is altered in leucine rich repeat kinase 2 mutant induced pluripotent stem cell derived neural cells

Author
item CANDELARIO, KATE - University Of Florida
item BALAJ, LEONORA - Harvard University
item ZHENG, TONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SKOG, JOHAN - Exosome Diagnostics
item BREAKEFIELD, XANDRA - Harvard University
item SCHULE, BIRGITT - Parkinson'S Institute And Clinical Center
item STEINDLER, DENNIS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Comparative Neurology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2019
Publication Date: 11/30/2019
Citation: Candelario, K.M., Balaj, L., Zheng, T., Skog, J., Breakefield, X., Schule, B., Steindler, D. 2019. Exosome/microvesicle content is altered in leucine rich repeat kinase 2 mutant induced pluripotent stem cell derived neural cells. Journal of Comparative Neurology. https://doi.org/10.1002/cne.24819.
DOI: https://doi.org/10.1002/cne.24819

Interpretive Summary: There is a pressing need to identify highly sensitive biomarkers of neurological disorders, especially those that accompany aging and where earliest diagnosis can lead to better, more precise therapies including standard of care and emerging and integrated medicine therapies including diet and nutrition. With a goal of identifying earliest disease onset in the neurodegenerative diseases, including Parkinson's and Alzheimer's, this study has focused on small vesicles called "exosomes" that all cells release, especially when they are stressed. Exosomes represent biomarkers of disease risk and progression and were studied from different Parkinson's disease brain tissue sources, and especially from the most common genetic mutation associated with Parkinson's disease, the Leucine-Rich Kinase 2 (LRRK2) gene, which was studied using patient induced pluripotent stem cells (iPSCs). Exosome molecular profiling revealed stem cell-related gene pathways that are altered in Parkinson's disease but that can be reversed using gene-editing approaches such that the exosome cargoes then exhibited normal expression patterns. This study shows that exosomes can serve as sensitive biomarkers of disease state in Parkinson's disease patients, and that following gene-editing exosomes reflects a corrected state with their molecular biographies of cargoes mirroring disease state and relevance for both prodromal and already symptomatic patient populations. Follow up studies focus on responses to disease-preventing/delaying standard of care and emerging therapies that can be monitored via non-invasive liquid biopsies from blood and examining exosome cargoes for disease- or therapy-related effects.

Technical Abstract: Extracellular vesicles, including exosomes and other microvesicles (EMVs), have been described as sensitive biomarkers that represent cell/tissue, cancer and degenerative disease states and responses to therapies. In light of recent reports of disease-mirroring EMV molecular signatures, that include pathological proteins and nucleic acids, implicating an infectious disease-like transmission in Parkinson's, Alzheimer's, and glioblastoma, the present study profiled EMVs from different Parkinson's disease (PD) tissue sources: neural progenitor cells derived from an endogenous adult stem/progenitor cell called an adult human neural progenitor cell (AHNP), that we found to be pathological when isolated from postmortem PD patients' substantia nigra; and from Leucine-Rich Kinase 2 (LRRK2) mutant gene identified human induced pluripotent stem cells (iPSCs), which were used to isolate EMVs and begin to characterize their cargoes. Initial characterization of exosomes derived from idiopathic (AHNPs) and mutant LRRK2 patients showed differences between both phenotypes and when compared to a sibling control in exosomal size and release based on Nanosight analysis. Furthermore, molecular profiling disclosed stem cell-related gene pathways that are altered in PD but that can be reversed using gene-editing approaches such that the EMV cargo genes then exhibited normal expression patterns. Finally, following transplantation of iPSC-derived neural progenitors in the adult mouse striatum, the cells were found to survive and differentiate into neurons. 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 with their molecular biographies of cargoes mirroring disease state and relevance for both prodromal and already symptomatic patient populations where potential responses to disease-preventing/delaying standard of care and emerging molecular and biological therapies can be monitored via non-invasive liquid biopsies and EMV characterizations.