Abstract
BackgroundMicrotubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein.MethodsHere, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization.ResultsHDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level.ConclusionsHDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases.BbeLHN_zgyG8Hf4zoSkS1nVideo abstract
Highlights
Microtubule-associated protein Tau undergoes aggregation in Alzheimers disease (AD) and a group of other related diseases collectively known as Tauopathies
The cell viability analysis carried out by MTT assay showed no noticeable decrease in viability, which was maintained at 80% even in the presence of highest Histone deacetylase-6 (HDAC6) ZnF HDAC6 zinc finger ubiquitin binding protein domain (UBP) concentration of 500 nM (Additional file 1: Fig. 1B)
We studied the role of HDAC6 ZnF UBP domain in different aspects of AD pathology
Summary
Microtubule-associated protein Tau undergoes aggregation in Alzheimers disease (AD) and a group of other related diseases collectively known as Tauopathies. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein. One of the major functions of HDAC6 is recruitment of polyubiquitinated protein aggregates to Dynein/Dynactin complex to sequester them to microtubule organizing centre (MTOC) in the perinuclear region for aggresome formation, thereby facilitating their clearance by autophagy [8,9,10]. Another important function of HDAC6 is the promotion of autophagosome-lysosome fusion and completion of autophagy [11,12,13]. The possible role of HDAC6 ZnF UBP in directly modulating the aggregation propensity and stability of Tau has been recently reported [16]
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