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Parkinson's disease patient-specific neuronal networks carrying the LRRK2 G2019S mutation unveil early functional alterations that predate neurodegeneration.

ABSTRACT: A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.

SUBMITTER: Carola G

PROVIDER: S-EPMC8253775 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Human iPSC-derived microglia carrying the LRRK2-G2019S mutation show a Parkinson's disease related transcriptional profile and function.

Project description:LRRK2-G2019S is one of the most common Parkinson's disease (PD)-associated mutations and has been shown to alter microglial functionality. However, the impact of LRRK2-G2019S on transcriptional profile of human induced pluripotent stem cell-derived microglia-like cells (iMGLs) and how it corresponds to microglia in idiopathic PD brain is not known. Here we demonstrate that LRRK2-G2019S carrying iMGL recapitulate aspects of the transcriptional signature of human idiopathic PD midbrain microglia. LRRK2-G2019S induced subtle and donor-dependent alterations in iMGL mitochondrial respiration, phagocytosis and cytokine secretion. Investigation of microglial transcriptional state in the midbrains of PD patients revealed a subset of microglia with a transcriptional overlap between the in vitro PD-iMGL and human midbrain PD microglia. We conclude that LRRK2-G2019S iMGL serve as a model to study PD-related effects in human microglia.

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Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila.

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Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids.

Project description:Recent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery.

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The Parkinson's disease associated mutation LRRK2-G2019S affects astrocyte specification

Project description:We report the altered transcriptomic profile of astrocytes in midbrain organoids differentiated for 35 and 70 days and generated from a stem cell line carrying the LRRK2-G2019S mutation compared to the isogenic pair.

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Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor.

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Gene expression profile of iPSC-derived dopaminergic neurons from control and Parkinson's disease patients carrying LRRK2 G2019S point mutation

Project description:The goal of this study is to compare the RNA expression profile from human iPSC-derived dopaminergic neurons from control, Parkinson’s disease LRRK2 G2019S and gene-edited isogenic lines (with corrected LRRK2 mutation) to gain insight into the mechanisms underlying neuronal degeneration in PD. Total RNA was assayed for quantity and quality using Qubit® RNA HS Assay (Life Technologies) and RNA 6000 Nano Assay on a Bioanalyzer 2100. All the steps were carried out in the ice and using the nCounter nanoString reagent for the Neuropathology panel. The master mix for the hybridization process was prepared by mixing hybridization buffer and reporter CodeSet. A dilution of 10μg/μl for each RNA to be analyzed was prepared and maintained in ice. For each sample, a tube was prepared with 5μl of RNA (10μg/μl) and 8μl of master mix. 2μl of Capture ProbeSet was added in each tube and the hybridization process was started using a PCR machine at 65ºC for at least 16 hours. After this step, the samples were maintained at 4ºC. Once the hybridization process was completed, the hybridized RNA was loaded in the neuropathology cartridge, and the data were available 24 hours later.

2021-02-24 | GSE167335 | GEO

RNA-sequencing (RNA-seq) of iPSC-derived astrocytes from control and Parkinson's disease patients carrying LRRK2 G2019S point mutation.

Project description:Purpose: The goal of this study is to compare the NGS-derived from transcriptome profiling (RNA-seq) of human iPSC-derived astrocytes from control and Parkinson’s disease LRRK2 G2019S to gain insight into the mechanisms driving astrocyte's alterations in PD.

2022-07-11 | GSE207713 | GEO

LRRK2 gene G2019S mutation and SNPs [haplotypes] in subtypes of Parkinson's disease.

Project description:Mutation within the leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a cause of autosomal dominant Parkinson's disease (PD). The purpose of this study was to determine the frequency of G2019S mutation and whether the differences in the allele and genotype distribution of six SNPs within LRRK2 gene are associated with PD in an American non-Hispanic white population. The sample included 350 sporadic PD (SPD), 225 familial PD (FPD) patients and 186 controls of the same race and ethnicity. The frequency of LRRK2 G2019S mutation in our total sample of PD (FPD and SPD) was 1.56%. The frequency of this mutation was 3.5% in the FPD and 0.3% in the SPD groups, respectively. Allele and genotype frequencies of six SNPs were compared between PD and control samples. In addition, PD groups were categorized by sporadic PD (no family history), familial PD (first degree relative with PD) and age of onset (AON, <or=50 or >or=51years). The haplotypes of the six SNPs were also constructed for association analysis. After correction for multiple comparisons, there was no association between any SNPs (allele or genotype) and PD groups. One of the haplotypes was modestly associated with the combined PD (SPD and FPD) sample. There was also no association with age at onset of PD. Our study suggests that the LRRK2 gene may be a risk factor or the cause for a very small fraction of PD in American white population.

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Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.

Project description:Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

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