On the contribution of Tau phosphorylation to nuclear and cytoplasmic changes in human neuroblastoma cells
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Date
2023-08-09
Authors
Tabeshmehr, Parisa
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Abstract
Human tauopathies are characterized by intracellular aggregation of hyperphosphorylated tau
protein in neurons. Tau is involved in many cellular functions through its association with
microtubules and actin filaments. In tauopathies overstabilization of filamentous actin (f-actin)
leads to invagination of nuclear envelope. An intricate protein layer known as Nuclear Lamina
(NL) is located at the interface of inner layers of nuclear envelope and chromatin. NL is degraded
after nuclear envelope invagination, resulting in aberrant gene expression and re-emergence of
ancient retroviruses. It is not clear if inhibition of kinases involved in tau pathology can prevent
NL invagination and its downstream events.
In this study, we first established that overexpression of full-length tau (FL-Tau) and the 35kDa
C-terminal fragment (Tau35) in differentiated human neuroblastoma (dSH-SY5Y) cell lines
enhanced nuclear lamina invagination and overstabilization of filamentous actin; however, these
changes were significantly exacerbated in Tau35-overexpressing cells.
Application of two small molecule inhibitors of c-Jun N-terminal kinase (JNK) and glycogen
synthase kinase-3β (GSK-3β) reduced the extent of damages in tau-overexpressing cells. JNK
inhibitor significantly decreased NL invagination in dSH-SY5Y-FL-Tau and -Tau35 cells.
Furthermore, GSK-3β inhibition alleviated f-actin overstabilization in dSH-SY5Y-FL-Tau cells.
In conclusion, we identified that NL invagination and f-actin overstabilization could be modulated
by inhibition of involving kinases in tauopathies.
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Keywords
Tau, Tauopathy, Neurodegeneration, Alzheimer’s Disease, Dementia, Aging, MAPT, Cytoskeleton