Extracellular HDAC6 ZnF UBP domain enhances podosome-mediated neuronal migration

The increasing prevalence of Alzheimer’s 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.