Biology subjects

Desale, S. E.

Publications and source records attributed to Desale, S. E..

3 recordsLinked to original sources

bioRxiv2024

Extracellular HDAC6 ZnF UBP domain enhances podosome-mediated neuronal migration

The increasing prevalence of Alzheimers disease demands research into therapeutic strategies that go beyond Amyloid and Tau. Synaptic loss, neuritic loss, and microtubule destabilization due to misfolded Tau and dysfunctional signalling in the AD-affected neuron, all point toward understanding and targeting cytoskeletal dysregulation in AD. Here we present, an extensive study on the novel role of the ZnF UBP (Zinc Finger Ubiquitin Binding Protein) domain of HDAC6 (Histone Deacetylase 6) in actin remodelling in neurons. We have demonstrated this function through immunofluorescence colocalization analysis in actin-rich podosome structures. We have found that this HDAC6 domain induces increased localization of the actin polymerization proteins, Arp2 and WASP and the adaptor protein TKS5 in the podosome structures. We have also extended our work to understand the potential of this domain in enhancing the podosome-mediated migration of neuronal cells. It was thus established that HDAC6 ZnF UBP induces increased association of cytoskeletal proteins within the podosomes, conferring enhanced migration potential to neurons and presenting an interesting strategy to improve neuronal health.

cell biology↗

bioRxiv2024

Microglia undergoes chemokine receptor, CX3CR1-mediated internalization of extracellular Tau

In Alzheimers disease, the microtubule-associated protein, Tau misfolds to form aggregates and filaments in the intra- and extracellular region of neuronal cells. CX3CR1 receptor is involved in monomeric Tau internalization by directly binding to the receptor. In our study, we are interested in understanding the interaction of different pathological structures of Tau with microglial chemokine receptor, CX3CR1 and its role in CX3CR1-mediated Tau internalization by immunofluorescence assay. Co-immunoprecipitation further confirmed the receptor interaction with Tau oligomers and even aggregated filaments. We next determined the role of Tau as a chemoattractant in regulating the migration of microglia by wound healing assay. Further, immunolocalization studies of CX3CR1 with {beta}-arrestin proved the desensitization of CX3CR1 receptor upon Tau binding. Upon ligand interaction, GPCRs undergoes desensitization and encytosed to the cytosol. We have quantified the CX3CR1 internalization by measuring the membrane to cytosol intensity ratio of CX3CR1 receptor upon extracellular Tau exposure. In addition to experimental assays, a comprehensive analysis of the interaction between the CX3CR1 receptor, the Tau protein, and the AZD8797 ligand has been derived from the combined molecular docking, molecular dynamics and free energy calculations using molecular mechanics-generalized Born approach. In particular, two different molecular dynamics simulations were carried out for CX3CR1-Tau protein and AZD8797-bound CX3CR1-Tau protein interaction. The molecular modeling study establishes that AZD8797 binds to CX3CR1 receptor and modulates the Tau interaction with the receptor.

cell biology↗

bioRxiv2020

α- Linoleanic acid modulates phagocytosis of extracellular Tau and induces microglial migration by actin-remodeling

The seeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimers disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions that influence various receptors expression and signaling cascade. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory properties to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The increased phagocytosis of extracellular Tau monomer and aggregates has been observed upon ALA exposure to microglia cells. The intracellular degradation of internalized Tau species was targeted by early and late endosomal markers Rab5 and Rab7. The increased levels of LAMP-2A and colocalization with internalized Tau indicated the degradation via lysosome. These results indicate the degradation of internalized Tau species in the presence of ALA instead of getting accumulated in the cell. The enhanced migratory ability of microglia in the presence of ALA induces the MTOC repolarization. Tau seeds greatly contribute to the spread of disease, one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids. Our results suggest that dietary fatty acids ALA significantly enhances phagocytosis and intracellular degradation of internalized Tau. Enhanced migration supports the phagocytosis process. Our approach provides insights into the beneficial role of ALA as an anti-inflammatory dietary supplement to treat AD.

neuroscience↗