Biology subjects

Paganetti, P.

Publications and source records attributed to Paganetti, P..

8 recordsLinked to original sources

bioRxiv2025

High Tau Expression Correlates with Reduced Invasion and Prolonged Survival in Ewing Sarcoma

The microtubule-associated protein Tau (encoded by the MAPT gene) is linked to a family of neurodegenerative disorders defined as tauopathies, which are characterized by its brain accumulation in neurofibrillary tangles and neuropil threads. Newly described Tau functions comprise DNA protection, chromatin remodeling, p53 regulation and cell fate modulation, suggesting a role of Tau in oncogenesis. Bioinformatic-supported characterization of Tau in cancer reveals robust expression in bone cancer cells, in particular Ewing sarcoma (EwS) cell lines. EwS is an aggressive cancer caused by a fusion of members of the FET and ETS gene families, primarily EWSR1::FLI1. Here we found that MAPT is a EWSR1::ETS target gene and that higher Tau expression in EwS cells inhibited their migratory and invasive behavior, consistent with a more immobile and proliferative phenotype observed in EwS. Indeed, we report that high Tau expression is associated with improved overall survival of EwS patients. We also show that the sessile but proliferative phenotype of EWSR1::ETS-high cells may result from a modulatory role of Tau on focal adhesion to extracellular matrix proteins. Our data highlight the utility of determining Tau expression as a prognostic factor in EwS as well as the opportunity to target Tau expression as an innovative EwS therapy.

cancer biology↗

bioRxiv2024

A new screening assay reveals that aminoglycoside antibiotics interfere with the Tau/MDM2 interaction

MAPT gene mutations cause some neurodegenerative tauopathies and the MAPT-encoded protein Tau is deposited in neurofibrillary tangles, hallmarks of this disease family. In addition to its canonical function in regulating microtubule dynamics, Tau modulates chromatin compaction, gene expression, and the cellular response to DNA damage. During the DNA damage response, Tau positively modulates P53 by binding to MDM2 thereby preventing P53 inactivation and degradation. The aberrant presence of both MDM2 associated to neurofibrillary tangles and of P53 misfolding in brains affected by neurodegenerative diseases suggests that the sequestration of MDM2 may prevent P53 clearance in tauopathies and so contribute to progressive neuronal dysfunction and death. Following this evidence, a pharmacological inhibition of the Tau/MDM2 interaction may represent a viable strategy to reduce P53-dependent cell damage in brain disorders. With the screening FDA-approved drugs and natural compounds, we discovered that members of the aminoglycoside antibiotic family antagonize the Tau/MDM2 interaction. The use of these reagents may advance the understanding of the implication of the Tau/MDM2/P53 axis in neurodegeneration models. However, their unfavorable pharmacokinetic properties may limit their systemic use when targeting the brain.

cell biology↗

bioRxiv2024

Pharmacological GCase Activity Enhancement Inhibits Tau Accumulation

A slow decline in the autophagy-lysosomal pathway is a hallmark of the normal aging brain. Yet, an acceleration of this cellular function may propel neurodegenerative events. In fact, mutations in genes associated with the autophagy-lysosomal pathway can lead to Parkinsons disease. Also, amyloidogenic protein deposition is observed in lysosomal storage disorders, which are caused by genetic mutations representing risk factors for Parkinsons disease. For example, Gauchers disease GBA1 mutations leading to defects in lysosomal sphingolipid metabolism cause -synuclein accumulation. We observed that increased lysosomal Tau accumulation is found in human dermal fibroblasts engineered for inducible Tau expression. Inhibition of the GBA1 product GCase augmented Tau-dependent lysosomal stress and Tau accumulation. Here, we show increased Tau seed-induced Tau accumulation in Gauchers fibroblasts carrying GBA1 mutations when compared to normal fibroblasts. Pharmacological enhancement of GCase reversed this effect, notably, also in normal fibroblasts. This suggests that boosting GCase activity may represent a therapeutic strategy to slow down aging-dependent lysosomal deficits and brain protein deposition.

cell biology↗

bioRxiv2023

Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Tau (MAPT) is a microtubule-associated protein causing common neurodegenerative diseases or inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA repair and P53 regulation suggests its involvement in cancer. Indeed, preliminary studies have correlated Tau expression with cancer survival or response to therapies. To bring new evidence for a relevant role of Tau in cancer, we carried out an in silico pan-cancer analysis of MAPT transcriptomic profile in over 10000 clinical samples from 32 cancer types and over 1300 pre-clinical samples from 28 cancer types provided by the TCGA and the DEPMAP datasets respectively. MAPT expression associated with key cancer hallmarks including inflammation, proliferation, and epithelial to mesenchymal transition, showing cancer-specific patterns. In some cancer types, MAPT functional networks were affected by P53 mutational status. We identified new associations of MAPT with clinical outcomes and drug response in a context-specific manner. Overall, our findings indicate that the MAPT gene is a potential major player in multiple types of cancer. Importantly, the impact of Tau on cancer seems to be heavily influenced by the specific cellular environment.

cancer biology↗

bioRxiv2023

Tau protein modulates an epigenetic mechanism of cellular senescence

Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimers 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 {beta}-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. 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. 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 complex and a lower histone 3 trimethylation activity 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. Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.

cell biology↗

bioRxiv2022

TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies

Aggregation of the RNA-binding protein TDP-43 is the main common neuropathological feature of TDP-43 proteinopathies. In physiological conditions, TDP-43 is predominantly nuclear and contained in biomolecular condensates formed via liquid-liquid phase separation (LLPS). However, in disease, TDP-43 is depleted from these compartments and forms cytoplasmic or, sometimes, intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Here, we show that self-oligomerization and RNA binding cooperatively govern TDP-43 stability, functionality, LLPS and cellular localization. Importantly, our data reveal that TDP-43 oligomerization is connected to, and conformationally modulated by, RNA binding. Mimicking the impaired proteasomal activity observed in patients, we found that TDP-43 forms nuclear aggregates via LLPS and cytoplasmic aggregates via aggresome formation. The favored aggregation pathway depended on the TDP-43 state -monomeric/oligomeric, RNA-bound/-unbound- and the subcellular environment -nucleus/cytoplasm. Our work unravels the origins of heterogeneous pathological species occurring in TDP-43 proteinopathies.

cell biology↗

bioRxiv2021

Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds

Many efforts targeting amyloid-{beta} (A{beta}) plaques for the treatment of Alzheimers Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-A{beta} treatments through high-resolution light-sheet imaging of electrophoretically-cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to {beta}-secretase inhibitors, polythiophenes, or anti-A{beta} antibodies. Each treatment showed unique spatiotemporal A{beta} clearance, with polythiophenes emerging as a potent anti-A{beta} compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each A{beta} therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of A{beta} plaques. This may also contribute to the clinical trial failures of A{beta}-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.

neuroscience↗

bioRxiv2020

Extracellular Vesicles Hijack the Autophagic Pathway to Induce Tau Accumulation in Endolysosomes

Clinical progression of tauopathies is reflected by the transcellular propagation of pathogenic Tau seeds with the possible involvement of extracellular vesicles as transport vectors. However, the mechanism regulating extracellular vesicle cargo delivery to recipient cells is poorly understood. We established a cell model for investigating extracellular vesicle-delivery of membranes and proteins. In this model, extracellular vesicles are readily internalized and accumulate in endolysosomes. For the first time, we show that in this acidic compartment of recipient cells, extracellular vesicle-delivered Tau seeds cause the accumulation and abnormal folding of normal Tau by a process that requires the participation of autophagy. Endolysomes represent thus a cross-road where Tau seeds released from extracellular vesicles propagate on cellular Tau on its route for autophagy-mediated degradation, ultimately driving its accumulation, endolysosomal stress and cytotoxicity. Whilst, autophagy stimulation is considered as a viable solution to protect neurons from harmful cytosolic protein inclusions, our data suggest that this approach may favour the aberrant accumulation of neurodegeneration-associated proteins induced by exogenous pathogenic protein forms, with possible implications in the spreading of the disease.

cell biology↗