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Effects of TDP-43 overexpression on neuron proteome and morphology in vitro

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Atkinson, RAK ORCID: 0000-0002-9846-7738, Fair, HL, Wilson, R ORCID: 0000-0003-0152-4394, Vickers, JC ORCID: 0000-0001-5671-4879 and King, AE ORCID: 0000-0003-1792-0965 2021 , 'Effects of TDP-43 overexpression on neuron proteome and morphology in vitro' , Molecular and Cellular Neurosciences, vol. 114 , pp. 1-11 , doi: 10.1016/j.mcn.2021.103627.

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Abstract

TDP-43 is pathologically and genetically with associated amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The involvement of TDP-43 in the degeneration of neurons in these diseases are not yet well understood, however accumulating evidence shows involvement in neurite outgrowth, remodelling and in regulation of many components of the neuronal cytoskeleton. In order to investigate how alterations to TDP-43 expression levels may exert effects on the neuronal cytoskeleton, primary cortical neurons from transgenic mice overexpressing one or two copies of human wildtype TDP-43 under the prion promoter were examined. Label-free quantitative proteomic analysis, followed by functional annotation clustering to identify protein families that clustered together within up- or down-regulated protein groups, revealed that actin-binding proteins were significantly more abundant in neurons overexpressing TDP-43 compared to wildtype neurons. Morphological analysis demonstrated that during early development neurons expressing one copy of human TDP-43 had an increased number of neurite branches and alterations to growth cone morphology, while no changes were observed in neurons expressing two copies of TDP-43. These developmental processes require specific expression and organization of the cytoskeleton. The results from these studies provide further insight into the normal function of TDP-43 and how alterations in TDP-43 expression may impact the cytoskeleton.

Item Type: Article
Authors/Creators:Atkinson, RAK and Fair, HL and Wilson, R and Vickers, JC and King, AE
Keywords: TDP-43, neuron morphology, proteomics, ALS, FTD
Journal or Publication Title: Molecular and Cellular Neurosciences
Publisher: Academic Press Inc Elsevier Science
ISSN: 1044-7431
DOI / ID Number: 10.1016/j.mcn.2021.103627
Copyright Information:

Copyright 2021 Elsevier Inc. All rights reserved Author accepted manuscript made available by permission of the publisher under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/

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