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000282566 037__ $$aDZNE-2025-01329
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000282566 1001_ $$aKnab, Felix$$b0
000282566 245__ $$aCellular and Extracellular MicroRNA Dysregulation in LRRK2-Linked Parkinson's Disease.
000282566 260__ $$aTotowa, NJ$$bHumana Press$$c2025
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000282566 520__ $$aCell-free microRNAs in body fluids have emerged as promising biomarker candidates in neurodegenerative diseases. While several studies have identified dysregulated miRNAs in sporadic Parkinson's disease, it remains unclear whether distinguishable alterations of cell-free miRNAs occur in genetic forms of the disease, such as those associated with the LRRK2 G2019S mutation. In this proof-of-concept study, we used a human induced pluripotent stem cell-derived dopaminergic neuron model to investigate whether the LRRK2 G2019S mutation induces detectable changes in the intra- and extracellular miRNAome, and whether miRNA signatures identified in vitro can be validated in patient-derived cerebrospinal fluid. We differentiated dopaminergic neurons from induced pluripotent stem cells carrying the LRRK2 G2019S mutation and an isogenic gene-corrected control. Extracellular vesicles were isolated from the culture medium and used as a source of cell-free miRNA. Next, small RNA libraries were generated and analyzed. Differentially expressed microRNAs were validated in an independent batch using RT-qPCR. We further quantified candidate microRNAs in cerebrospinal fluid samples from five LRRK2 G2019S patients and matching healthy controls. The patient cohort included the fibroblast donor from whom the stem cells were originally derived. We successfully isolated extracellular vesicles from induced pluripotent stem cell-derived human dopaminergic neurons. We identified a distinct set of differentially expressed miRNAs in cellular and cell-free RNA, among which let-7g-5p and miR-21-5p were consistently upregulated and validated across independent replicates. These alterations were reflected in the cerebrospinal fluid of the original donor and partially reproduced in additional LRRK2 patients, supporting the concept of patient-specific signatures. A strong correlation between intra- and extracellular miRNA expression was observed. Our findings demonstrate that induced pluripotent stem cell-derived dopaminergic neurons can serve as a model to identify individualized, cell-free microRNA signatures associated with the LRRK2 G2019S mutation. The dysregulated miRNAs detected in vitro were mirrored in patient cerebrospinal fluid, supporting their potential as accessible molecular readouts. These results lay the groundwork for personalized biomarker strategies in genetic forms of Parkinson's disease and warrant further validation in larger patient cohorts.
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000282566 650_7 $$2Other$$aBiomarker
000282566 650_7 $$2Other$$aIPSCs
000282566 650_7 $$2Other$$aLRRK2
000282566 650_7 $$2Other$$aMicro-RNA
000282566 650_7 $$2Other$$aParkinson’s disease
000282566 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000282566 650_7 $$2NLM Chemicals$$aMicroRNAs
000282566 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLRRK2 protein, human
000282566 650_2 $$2MeSH$$aHumans
000282566 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000282566 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
000282566 650_2 $$2MeSH$$aMicroRNAs: genetics
000282566 650_2 $$2MeSH$$aMicroRNAs: metabolism
000282566 650_2 $$2MeSH$$aMicroRNAs: cerebrospinal fluid
000282566 650_2 $$2MeSH$$aParkinson Disease: genetics
000282566 650_2 $$2MeSH$$aParkinson Disease: cerebrospinal fluid
000282566 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000282566 650_2 $$2MeSH$$aDopaminergic Neurons: metabolism
000282566 650_2 $$2MeSH$$aDopaminergic Neurons: pathology
000282566 650_2 $$2MeSH$$aExtracellular Vesicles: metabolism
000282566 650_2 $$2MeSH$$aMutation: genetics
000282566 650_2 $$2MeSH$$aCell Differentiation
000282566 650_2 $$2MeSH$$aMiddle Aged
000282566 650_2 $$2MeSH$$aMale
000282566 650_2 $$2MeSH$$aFemale
000282566 7001_ $$aLee, Jun-Hoe$$b1
000282566 7001_ $$aNirujogi, Raja$$b2
000282566 7001_ $$aMenden, Kevin$$b3
000282566 7001_ $$aBraunger, Luca$$b4
000282566 7001_ $$0P:(DE-2719)9003552$$aLogarnudi, Lambrianna$$b5$$udzne
000282566 7001_ $$0P:(DE-2719)9000377$$aRiebenbauer, Benjamin$$b6
000282566 7001_ $$aIsik, Fatma Busra$$b7
000282566 7001_ $$aRajkumar, Anto Praveen$$b8
000282566 7001_ $$aCzemmel, Stefan$$b9
000282566 7001_ $$aFitzgerald, Julia$$b10
000282566 7001_ $$0P:(DE-2719)2320009$$aGasser, Thomas$$b11$$eLast author$$udzne
000282566 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian Johannes$$b12$$eLast author$$udzne
000282566 773__ $$0PERI:(DE-600)2079384-4$$a10.1007/s12035-025-05379-2$$gVol. 63, no. 1, p. 189$$n1$$p189$$tMolecular neurobiology$$v63$$x0893-7648$$y2025
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