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Investigating TDP-43 palmitoylation as a therapeutic target to lower protein aggregation

Project Overview

TDP-43 (transactive response DNA-binding protein 43) is one of the few genes highly associated with ALS (amyotrophic lateral sclerosis). Although TDP-43 mutations only occur in a small subset of ALS patients, cytoplasmic inclusions that mainly consists of TDP-43 protein aggregates are present in 97% of all ALS cases as well in a notable number of additional neurodegenerative diseases. Therefore, targeting TDP-43 toxicity arising from its cytoplasmic mislocalization and aggregation, is an important pathway to understand the underlying pathogenic mechanisms of ALS and other proteinopathies. Herein, I propose the first study to examine the role of protein palmitoylation as a regulatory mechanism of TDP-43 mislocalization, affecting its subcellular localization, aggregation and proteostasis. Protein palmitoylation consists of the covalent addition of a fatty acid to cysteine residues of target proteins and has been strongly implicated in protein trafficking and membrane-related cellular processes. I have experimentally confirmed TDP-43 palmitoylation using alkynyl palmitate labeling and click chemistry detection, which is a novel finding. The same experiment showed the presence of smaller fragments, one of which is also palmitoylated, suggesting a connection to caspase cleavage. In addition, TDP-43 depalmitoylation inhibitor Palmostatin B upregulated TDP-43 S-nitrosylation, suggesting a regulatory relationship between the two cysteine modifications. I hypothesize TDP-43 palmitoylation to have a positive regulatory role in TDP-43 nitrosylation as well as caspase cleavage, thereby contributing to cytoplasmic aggregation and ALS pathology. My research aims to first characterize TDP-43 palmitoylation and its effect in ALS by elucidating the sites and enzymes of palmitoylation, then to investigate the interrelationship of palmitoylation within the TDP-43 post-translational modifications network. The proposed research will provide foundational insight on a novel mechanism to further our understanding of ALS pathogenesis.

Team Members

Lucia Liao, University of Waterloo

Partners and Donors

ALS Society of Canada

Project Ongoing

Investigating TDP-43 palmitoylation as a therapeutic target to lower protein aggregation

  • Program Type

    Capacity building grants

  • Area of research

    Neurodegeneration

  • Disease Area

    ALS

  • Competition

    ALS Canada-Brain Canada Trainee Program 2022

  • Province

    Ontario

  • Start Date

    2022

  • Total Grant Amount

    $75,000

  • Health Canada Contribution

    $37,500

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