Expression of the Parkinson’s Disease-Associated Gene Alpha-Synuclein is Regulated by the Neuronal Cell Fate Determinant TRIM32

Alpha-synuclein is an abundant neuronal protein which has been associated with physiological processes like synaptic function, neurogenesis, and neuronal differentiation but also with pathological neurodegeneration. Indeed, alpha-synuclein (snca) is one of the major genes implicated in Parkinson’s disease (PD). However, little is known about the regulation of alpha-synuclein expression. Unveiling the mechanisms that control its regulation is of high importance, as it will enable to further investigate and comprehend the physiological role of alpha-synuclein as well as its potential contribution in the aetiology of PD. Previously, we have shown that the protein TRIM32 regulates fate specification of neural stem cells. Here, we investigated the impact of TRIM32 on snca expression regulation in vitro and in vivo in neural stem cells and neurons. We demonstrated that TRIM32 is positively influencing snca expression in a neuronal cell line, while the absence of TRIM32 is causing deregulated levels of snca transcripts. Finally, we provided evidence that TRIM32 binds to the promoter region of snca, suggesting a novel mechanism of its transcriptional regulation. On the one hand, the presented data link the PD-associated gene alpha-synuclein to the neuronal cell fate determinant TRIM32 and thereby support the concept that PD is a neurodevelopmental disorder. On the other hand, they imply that defects in olfactory bulb adult neurogenesis might contribute to early PD-associated non-motor symptoms like hyposmia.The J. C. S.’s lab is supported by the Boehringer Ingelheim Foundation and the fund “Innovative Medical Research” of the University of Münster Medical School, Schram-Stiftung (T287/21795/2011) by the Fonds National de la Recherche (FNR) Luxembourg (CORE, C13/BM/5791363), a University Luxembourg Internal Research Project (MidNSCs) and the EU Joint Programme - Neurodegenerative Disease Research (JPND) project (supported by the FNR). L.G.C. was supported by a fellowship from the FNR (AFR, Aides à la Formation-Recherche). M.C.M ’s lab is supported by Grant SAF2012-36143 from Spanish Ministerio de Ciencia e and LE310U14 from the Junta de Castilla y Leon. S.F.A holds a predoctoral contract (PIRTU) from Junta de Castilla y Leon

Kohlenstoff-Einlagerung und -Freisetzung in bis zu 200.000 Jahre alten Böden in Nordsibirien.

Auf Bol'shoy Lyakhovsky, die südlichste der Neusibirischen Inseln, wurden fünf Bohrkerne mit einer Gesamtlänge von 52 m gewonnen. Sie erfassen Permafrostböden aus dem Holozän bis zurück ins Prä-Eem (ca. 200 Tausend Jahre vor heute). Die z.Zt. laufenden geowissenschaftlichen Analysen der Kerne beinhalten sedimentologische, geophysikalische, biogeochemische und mikrobiologische Techniken. Hauptziel des Projektes ist es, die aktuelle natürliche Produktion von Treibhausgasen in Permafrostböden zu bewerten, um eine künftige Treibhausgasproduktion in einer wärmer werdenden Arktis besser abzuschätzen. Die heutigen Raten der Treibhausgasproduktion werden dabei mit Signalen des Abbaus organischer Substanz in den zurückliegenden zwei Glazial-Interglazial-Zyklen in Beziehung gesetzt. Diese Studie ist Teil des deutsch-russischen Gemeinschaftsprojektes CARBOPERM, das mehr als 50 Wissenschaftler aus verschiedenen Instituten in Deutschland und Russland verbindet. Das 3-Jahres-Projekt widmet sich dem besseren Verständnis der Bildung, Umwandlung und Freisetzung von organischem Kohlenstoff in nordsibirischen Permafrostlandschaften

Millifluidic culture improves human midbrain organoid vitality and differentiation

Human midbrain-specific organoids (hMOs) serve as an experimental in vitro model for studying the pathogenesis of Parkinson's disease (PD). In hMOs, neuroepithelial stem cells (NESCs) give rise to functional midbrain dopaminergic (mDA) neurons that are selectively degenerating during PD. A limitation of the hMO model is an under-supply of oxygen and nutrients to the densely packed core region, which leads eventually to a "dead core". To reduce this phenomenon, we applied a millifluidic culture system that ensures media supply by continuous laminar flow. We developed a computational model of oxygen transport and consumption in order to predict oxygen levels within the hMOs. The modelling predicts higher oxygen levels in the hMO core region under millifluidic conditions. In agreement with the computational model, a significantly smaller "dead core" was observed in hMOs cultured in a bioreactor system compared to those ones kept under conventional shaking conditions. Comparing the necrotic core regions in the organoids with those obtained from the model allowed an estimation of the critical oxygen concentration necessary for ensuring cell vitality. Besides the reduced "dead core" size, the differentiation efficiency from NESCs to mDA neurons was elevated in hMOs exposed to medium flow. Increased differentiation involved a metabolic maturation process that was further developed in the millifluidic culture. Overall, bioreactor conditions that improve hMO quality are worth considering in the context of advanced PD modelling

Single-cell sequencing of the human midbrain reveals glial activation and a neuronal state specific to Parkinson's disease

Parkinson's disease (PD) etiology is associated with genetic and environmental factors that lead to a loss of dopaminergic neurons. However, the functional interpretation of PD-associated risk variants and how other midbrain cells contribute to this neurodegenerative process are poorly understood. Here, we profiled >41,000 single-nuclei transcriptomes of postmortem midbrain tissue from 6 idiopathic PD (IPD) patients and 5 matched controls. We show that PD-risk variants are associated with glia- and neuron-specific gene expression patterns. Furthermore, Microglia and astrocytes presented IPD-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. IPD-microglia revealed a specific pro-inflammatory trajectory. Finally, we discovered a neuronal cell cluster exclusively present in IPD midbrains characterized by CADPS2 overexpression and a high proportion of cycling cells. We conclude that elevated CADPS2 expression is specific to dysfunctional dopaminergic neurons, which have lost their dopaminergic identity and unsuccessful attempt to re-enter the cell cycle

Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection

Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169+ sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4+CD25+ T cells and an increased number of B220+CD19+ B cells. The reduction in CD4+CD25+ T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome