Development of the TDP43-proteinopathia cell model to search approaches to pathogenic therapy of the Frontotemporal Lobar Degeneration

Abstract

Change in compartmentalization of TDP43 protein, loss of its nuclear localization, and the protein loading in the cytoplasm, where it forms aggregates, are the important pathogenic factors of molecular dysfunction development during the TDP43-proteinopathies. Inhibition of the pathogenic protein’s aggregation is considered now as a perspective approach to development of the methods of pathogenic therapy of neurodegenerative diseases caused by the proteinopathies. Development of convenient cell models, which are more adequately reproduce molecular mechanism of the protein’s aggregation typical for the proteinopathies allows significant optimization of the development of compounds, which can specifically suppress or block different stages of the proteinopathy. The present work demonstrates the development of the original model of the TDP43-proteinopathy in the culture of human neuroblastoma SH-SY5Y cells with formation of typical TDP43-reactive structures, imitating pathogistological inclusions, which are revealed in tissue autopsy of patients with different forms of FLD. Russian preparation Dimebon with the neuroprotective effect can inhibit formation of the TDP43-reactive inclusions in this cell model. It can be assumed as the potential compound, based on which the development of methods of the pathogenic therapy of TDP43-proteinopathy is possible, and some of the FLD forms, particularly.