Modeling Parkinson’s disease in midbrain-like organoids

in NPJ Parkinson's Disease (2019)

In vivo Phenotyping of Human Parkinson’s Disease-Specific Stem Cells Carrying the LRRK2-G2019S Mutation Reveals Increased a-Synuclein Levels but Absence of Spreading

in Opera Medica et Physiologica (2018)

A systemic transcriptome analysis reveals the regulation of neural stem cell maintenance by an E2F1-miRNA feedback loop.

in Nucleic Acids Research (2013), 41(6), 3699-712

Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC ... [more ▼]

Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC) maintenance and neuronal commitment, we performed a high-throughput mRNA and miRNA profiling and isolated functional interaction networks of involved mechanisms. Thereby, we identified an E2F1-miRNA feedback loop as important regulator of NSC fate decisions. Although E2F1 supports NSC proliferation and represses transcription of miRNAs from the miR-17 approximately 92 and miR-106a approximately 363 clusters, these miRNAs are transiently up-regulated at early stages of neuronal differentiation. In these early committed cells, increased miRNAs expression levels directly repress E2F1 mRNA levels and inhibit cellular proliferation. In mice, we demonstrated that these miRNAs are expressed in the neurogenic areas and that E2F1 inhibition represses NSC proliferation. The here presented data suggest a novel interaction mechanism between E2F1 and miR-17 approximately 92 / miR-106a approximately 363 miRNAs in controlling NSC proliferation and neuronal differentiation. [less ▲]

JAM-C is an apical surface marker for neural stem cells.

in Stem Cells and Development (2012), 21(5), 757-66

Junctional adhesion molecule-C (JAM-C) is an adhesive cell surface protein expressed in various cell types. JAM-C localizes to the apically localized tight junctions (TJs) between contacting endothelial ... [more ▼]

Junctional adhesion molecule-C (JAM-C) is an adhesive cell surface protein expressed in various cell types. JAM-C localizes to the apically localized tight junctions (TJs) between contacting endothelial and epithelial cells, where it contributes to cell-cell adhesions. Just as those epithelial cells, also neural stem cells are highly polarized along their apical-basal axis. The defining feature of all stem cells, including neural stem cells (NSCs) is their ability to self renew. This self-renewal depends on the tight control of symmetric and asymmetric cell divisions. In NSCs, the decision whether a division is symmetric or asymmetric largely depends on the distribution of the apical membrane and cell fate determinants on the basal pole of the cell. In this study we demonstrate that JAM-C is expressed on neural progenitor cells and neural stem cells in the embryonic as well as the adult mouse brain. Furthermore, we demonstrate that in vivo JAM-C shows enrichment at the apical surface and therefore is asymmetrically distributed during cell divisions. These results define JAM-C as a novel surface marker for neural stem cells. [less ▲]

Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice.

in Stem Cell Research and Therapy (2012), 3(4), 33

ABSTRACT: INTRODUCTION: The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how ... [more ▼]

ABSTRACT: INTRODUCTION: The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration. METHODS: Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-alpha infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples. RESULTS: Here, we demonstrate that differences in the chronicity of TNF-alpha application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-alpha treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced. CONCLUSIONS: We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control. [less ▲]