Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells

Introduction: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation.Methods: To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells.Results: Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells.Discussion: Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging

Efficient cell death mediated by bioengineered killer extracellular vesicles

Abstract Extracellular vesicles (EVs) are biological vehicles that are thought to mediate cell–cell communication via the transfer of biomolecules from donor to acceptor cells. Repurposing those natural vesicles into therapeutics delivery vectors is a high priority challenge for translational science. Here we engineer donor cells to produce copious amount of fusogenic EVs loaded with the catalytic domain of the Diphteria Toxin, known to trigger cell death through protein synthesis inhibition. We show that, when incubated with cancer acceptor cells, these Killer EVs block protein synthesis and lead to cell death. This proof of concept establishes the efficacy of Killer EVs in vitro, and suggests that further development may lead to tumor ablation in vivo, expanding the existing cancer therapeutics arsenal

Extracellular Vesicles as Promising Carriers in Drug Delivery: Considerations from a Cell Biologist’s Perspective

The use of extracellular vesicles as cell-free therapy is a promising approach currently investigated in several disease models. The intrinsic capacity of extracellular vesicles to encapsulate macromolecules within their lipid bilayer membrane-bound lumen is a characteristic exploited in drug delivery to transport active pharmaceutical ingredients. Besides their role as biological nanocarriers, extracellular vesicles have a specific tropism towards target cells, which is a key aspect in precision medicine. However, the little knowledge of the mechanisms governing the release of a cargo macromolecule in recipient cells and the Good Manufacturing Practice (GMP) grade scale-up manufacturing of extracellular vesicles are currently slowing their application as drug delivery nanocarriers. In this review, we summarize, from a cell biologist’s perspective, the main evidence supporting the role of extracellular vesicles as promising carriers in drug delivery, and we report five key considerations that merit further investigation before translating Extracellular Vesicles (EVs) to clinical applications

TGFβ1 Induces Axonal Outgrowth via ALK5/PKA/SMURF1-Mediated Degradation of RhoA and Stabilization of PAR6

Transforming growth factor (TGF)β1 has repeatedly been associated with axonal regeneration and recovery after injury to the CNS. We found TGFβ1 upregulated in the stroke-denervated mouse spinal cord after ischemic injury to the motor cortex as early as 4 d postinjury (dpi) and persisting up to 28 dpi. Given the potential role of TGFβ1 in structural plasticity and functional recovery after stroke highlighted in several published studies, we investigated its downstream signaling in an in vitro model of neurite outgrowth. We found that in this model, TGFβ1 rescues neurite outgrowth under growth inhibitory conditions via the canonical TGFβR2/ALK5 signaling axis. Thereby, protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase SMURF1 induces a switch of its substrate preference from PAR6 to the Ras homolog A (RhoA), in this way enhancing outgrowth on the level of the cytoskeleton. This proposed mechanism of TGFβ1 signaling could underly the observed increase in structural plasticity after stroke in vivo as suggested by the temporal and spatial expression of TGFβ1. In accordance with previous publications, this study corroborates the potential of TGFβ1 and associated signaling cascades as a target for future therapeutic interventions to enhance structural plasticity and functional recovery for stroke patients

Tau accumulation in degradative organelles is associated to lysosomal stress

Abstract Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer’s disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher’s disease and a main risk for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD

Tau protein binds to the P53 E3 ubiquitin ligase MDM2

Abstract Tau gene mutations cause a progressive dementia and neurotoxic Tau forms deposited in neurofibrillary tangles are hallmarks of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. In fact, Tau depletion affects the cellular response to DNA damage and tauopathies exhibit the accumulation of DNA lesions. Moreover, Tau modulates P53 activity and cell fate. Considering that MDM2 is the main antagonist of P53, we investigated, using orthogonal assays, if Tau interacts with MDM2. We report the existence in cells and brain of a Tau-MDM2 complex that, in vitro, exhibits reduced P53 ubiquitination activity in a manner sensitive to a Tau mutation. The Tau-MDM2 interaction involves the microtubule-binding domain of Tau and the acidic domain of MDM2, reminiscent of the binding of Tau to negatively charged microtubules. Notably, MDM2 accumulates aberrantly in neurofibrillary tangles. Aging-associated insults may expose a novel loss-of-function of Tau in neurodegeneration and cancer

Extracellular vesicles containing ACE2 efficiently prevent infection by SARS‐CoV‐2 Spike protein‐containing virus

International audienceSARS-CoV-2 entry is mediated by binding of the spike protein (S) to the surface receptor ACE2 and subsequent priming by host TMPRSS2 allowing membrane fusion. Here, we produced extracellular vesicles (EVs) exposing ACE2 and demonstrate that ACE2-EVs are efficient decoys for SARS-CoV-2 S protein-containing lentivirus. Reduction of infectivity positively correlates with the level of ACE2, is much more efficient than with soluble ACE2 and further enhanced by the inclusion of TMPRSS2

Image1_Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells.jpg

Introduction: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation.Methods: To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells.Results: Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells.Discussion: Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.</p

Image3_Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells.TIF

Introduction: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation.Methods: To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells.Results: Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells.Discussion: Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.</p

Image2_Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells.tif

Introduction: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation.Methods: To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells.Results: Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells.Discussion: Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.</p