Exosome/microvesicle content is altered in leucine‐rich repeat kinase 2 mutant induced pluripotent stem cell‐derived neural cells

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.

Human Induced Pluripotent Stem Cell-Derived Exosomes as a New Therapeutic Strategy for Various Diseases

“…Candelario et al reported that two kinds of exosomes were found from different Parkinson's disease (PD) tissue sources [68]. One exosome was isolated from human neural progenitor (AHNP) cells from the substantia nigra of postmortem PD patients and the other was isolated from the leucine-rich repeat kinase 2 (LRRK2) gene identified in patient iPSCs.…”

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease

“…Additionally, in a recent study, Candelario and colleagues characterized EVs produced by: (i) DAergic neurons derived from induced pluripotent stem cells (iPSC) carrying the LRRK2 G2019S mutation; (ii) DAergic neurons derived from iPSC of healthy sibling control; and (iii) LRRK2 G2019S edited to correct the mutation [ 138 ]. They found that EVs from all cell types were different in size and abundance.…”

“…Interestingly, the G/S correction induced the secretion of EVs whose cargo pattern was similar to control ones. Therefore the authors suggested to further analyze the content of EVs to identify potential novel biomarkers for PD [ 138 ].…”

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism

“…LRRK2 could hold the key to unlocking answers as to why different neuropathological changes can arise from underlying genetic changes in this gene. Currently, the pathways and potential disease modifier genes that explain this striking pleomorphic presentation of LRRK2 parkinsonism and variable clinical penetrance/AAO are unknown, although many cellular phenotypes and molecular pathways, including endolysosomal stress [60][61][62], neuroinflammation [63][64][65], mitochondrial dysfunction and damage [66,67], and alterations of exosomes [68,69] have been described due to altered LRRK2 signaling. Mendelian PD genes, GWAS risk factors, and polygenic risk scores have been nominated as influencing factors for LRRK2, but studies that validate these putative modifiers are lacking.…”