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See detailPINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage.
Brunelli, Francesco; Torosantucci, Liliana; Gelmetti, Vania et al

in Cells (2022), 11(4),

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with ... [more ▼]

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson's disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the pro-apoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1-Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases. [less ▲]

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See detailNF-κB and TNF Affect the Astrocytic Differentiation from Neural Stem Cells
Grandbarbe, Luc UL; Michelucci, Alessandro UL; Heuschling, Paul UL et al

in Cells (2021)

The NF-κB signaling pathway is crucial during development and inflammatory processes. We have previously shown that NF-κB activation induces dedifferentiation of astrocytes into neural progenitor cells ... [more ▼]

The NF-κB signaling pathway is crucial during development and inflammatory processes. We have previously shown that NF-κB activation induces dedifferentiation of astrocytes into neural progenitor cells (NPCs). Here, we provide evidence  that the NF-κB pathway plays also a fundamental role during the differentiation of NPCs into astrocytes. First, we show that the NF-κB pathway is essential to initiate astrocytic differentiation as its early inhibition induces NPC apoptosis and impedes their differentiation. Second, we demonstrate that persistent NF-κB activation affects NPC-derived astrocyte differentiation. Tumor necrosis factor (TNF)-treated NPCs show NF-κB activation, maintain their multipotential and proliferation properties, display persistent expression of immature markers and inhibit astrocyte markers. Third, we analyze the effect of  NF-κB activation on the main known astrocytic differentiation pathways, such as NOTCH and JAK-STAT. Our findings suggest that the NF-κB pathway plays a dual fundamental role during NPC differentiation into astrocytes: it promotes astrocyte specification, but its persistent activation impedes their differentiation. [less ▲]

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See detailMapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts
Karta, Jessica UL; Bossicard, Ysaline UL; Kotzamanis, Konstantinos UL et al

in Cells (2021)

Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known ... [more ▼]

Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known to adapt their metabolism to sustain high proliferation rates and survive in unfavorable environments with low oxygen and nutrient concentrations. Hence, targeting cancer cell metabolism is a promising therapeutic strategy in cancer research. However, cancers consist not only of genetically altered tumor cells but are interwoven with endothelial cells, immune cells and fibroblasts, which together with the extracellular matrix (ECM) constitute the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which are linked to poor prognosis in different cancer types, are one important component of the TME. CAFs play a significant role in reprogramming the metabolic landscape of tumor cells, but how, and in what manner, this interaction takes place remains rather unclear. This review aims to highlight the metabolic landscape of tumor cells and CAFs, including their recently identified subtypes, in different tumor types. In addition, we discuss various in vitro and in vivo metabolic techniques as well as different in silico computational tools that can be used to identify and characterize CAF–tumor cell interactions. Finally, we provide our view on how mapping the complex metabolic networks of stromal-tumor metabolism will help in finding novel metabolic targets for cancer treatment. [less ▲]

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See detailAcanthocyte Sedimentation Rate as a Diagnostic Biomarker for Neuroacanthocytosis Syndromes: Experimental Evidence and Physical Justification.
Darras, Alexis; Peikert, Kevin; Rabe, Antonia et al

in Cells (2021), 10(4),

(1) Background: Chorea-acanthocytosis and McLeod syndrome are the core diseases among the group of rare neurodegenerative disorders called neuroacanthocytosis syndromes (NASs). NAS patients have a ... [more ▼]

(1) Background: Chorea-acanthocytosis and McLeod syndrome are the core diseases among the group of rare neurodegenerative disorders called neuroacanthocytosis syndromes (NASs). NAS patients have a variable number of irregularly spiky erythrocytes, so-called acanthocytes. Their detection is a crucial but error-prone parameter in the diagnosis of NASs, often leading to misdiagnoses. (2) Methods: We measured the standard Westergren erythrocyte sedimentation rate (ESR) of various blood samples from NAS patients and healthy controls. Furthermore, we manipulated the ESR by swapping the erythrocytes and plasma of different individuals, as well as replacing plasma with dextran. These measurements were complemented by clinical laboratory data and single-cell adhesion force measurements. Additionally, we followed theoretical modeling approaches. (3) Results: We show that the acanthocyte sedimentation rate (ASR) with a two-hour read-out is significantly prolonged in chorea-acanthocytosis and McLeod syndrome without overlap compared to the ESR of the controls. Mechanistically, through modern colloidal physics, we show that acanthocyte aggregation and plasma fibrinogen levels slow down the sedimentation. Moreover, the inverse of ASR correlates with the number of acanthocytes (R2=0.61, p=0.004). (4) Conclusions: The ASR/ESR is a clear, robust and easily obtainable diagnostic marker. Independently of NASs, we also regard this study as a hallmark of the physical view of erythrocyte sedimentation by describing anticoagulated blood in stasis as a percolating gel, allowing the application of colloidal physics theory. [less ▲]

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See detailUsing High-Content Screening to Generate Single-Cell Gene-Corrected Patient-Derived iPS Clones Reveals Excess Alpha-Synuclein with Familial Parkinson's Disease Point Mutation A30P.
Barbuti, Peter UL; Antony, Paul UL; Rodrigues Santos, Bruno UL et al

in Cells (2020), 9(9),

The generation of isogenic induced pluripotent stem cell (iPSC) lines using CRISPR-Cas9 technology is a technically challenging, time-consuming process with variable efficiency. Here we use fluorescence ... [more ▼]

The generation of isogenic induced pluripotent stem cell (iPSC) lines using CRISPR-Cas9 technology is a technically challenging, time-consuming process with variable efficiency. Here we use fluorescence-activated cell sorting (FACS) to sort biallelic CRISPR-Cas9 edited single-cell iPSC clones into high-throughput 96-well microtiter plates. We used high-content screening (HCS) technology and generated an in-house developed algorithm to select the correctly edited isogenic clones for continued expansion and validation. In our model we have gene-corrected the iPSCs of a Parkinson's disease (PD) patient carrying the autosomal dominantly inherited heterozygous c.88G>C mutation in the SNCA gene, which leads to the pathogenic p.A30P form of the alpha-synuclein protein. Undertaking a PCR restriction-digest mediated clonal selection strategy prior to sequencing, we were able to post-sort validate each isogenic clone using a quadruple screening strategy prior to generating footprint-free isogenic iPSC lines, retaining a normal molecular karyotype, pluripotency and three germ-layer differentiation potential. Directed differentiation into midbrain dopaminergic neurons revealed that SNCA expression is reduced in the gene-corrected clones, which was validated by a reduction at the alpha-synuclein protein level. The generation of single-cell isogenic clones facilitates new insights in the role of alpha-synuclein in PD and furthermore is applicable across patient-derived disease models. [less ▲]

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See detailHypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells
Ullmann, Pit; Nurmik, Martin UL; Begaj, Rubens UL et al

in Cells (2019), 8(6),

Colorectal cancer (CRC), the second most common cause of cancer mortality in theWestern world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as ... [more ▼]

Colorectal cancer (CRC), the second most common cause of cancer mortality in theWestern world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Over the past few years, a plethora of di erent approaches, aimed at identifying and eradicating these self-renewing TICs, have been described. A focus on the metabolic and bioenergetic di erences between TICs and less aggressive di erentiated cancer cells has thereby emerged as a promising strategy to specifically target the tumorigenic cell compartment. Extrinsic factors, such as nutrient availability or tumor hypoxia, are known to influence the metabolic state of TICs. In this review, we aim to summarize the current knowledge on environmental stress factors and how they a ect the metabolism of TICs, with a special focus on microRNA (miRNA)- and hypoxia-induced e ects on colon TICs. [less ▲]

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