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A role for SUMOylation in the Formation and Cellular Localization of TDP-43 Aggregates in Amyotrophic Lateral Sclerosis

Abstract

In amyotrophic lateral sclerosis, motor neurons undergoing degeneration are characterized by the presence of cytoplasmic aggregates containing TDP-43 protein. SUMOylation, a posttranslational modification of proteins, has been previously implicated in the formation of aggregates positives for SOD1, another protein enriched in a subset of ALS patients. We show in this study that TDP-43 is also a target of SUMOylation. The inhibition of the first step of the SUMOylation process by anacardic acid significantly reduces the presence of TDP-43 aggregates and improves neuritogenesis and cell viability in vitro. Interestingly, the mutation of the unique SUMOylation site on TDP-43, using site-directed mutagenesis, modifies the intracellular localization of TDP-43 aggregates. Instead of being cytoplasmic where they are associated with toxic effects, they are located inside the nucleus. This change of localization results in improvement in cell viability and in global cellular functions. Our results implicate the SUMOylation site of TDP-43 in the formation of cytoplasmic TDP-43 aggregates, a hallmark of ALS, and thus identifies this region as a new target for novel therapeutic strategies.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

AA:

Anacardic acid

FTD:

Fronto-temporal dementia

PTM:

Posttranslational modifications

RBPs:

RNA-binding proteins

SUMO:

Small ubiquitin-like modifier

SOD1:

Superoxide dismutase 1

TARDBP:

TAR DNA-binding protein

MAPT:

Microtubule-associated protein Tau

GAP43:

Growth-associated protein

MAP 2:

Microtubule-associated protein 2

VAChT:

Vesicular acetylcholine transporter

ChAT:

Choline O-acetyltransferase

AChE:

Acetylcholinesterase

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Acknowledgments

We thank A. Bennett for reading the manuscript. We thank the Département génomique of the plateform PST ASB, Université de Tours, for technical help. We thank Dr Frédéric Laumonnier for essential scientific advices and support towards this project.

Funding

This work was supported by a grant ARSLA; the Laboratory of Excellence (Labex) MabImprove; a PhD fellowship of the Region Centre Val-de-Loire France (CM).

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Correspondence to Cindy Maurel.

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Maurel, C., Chami, A., Thépault, RA. et al. A role for SUMOylation in the Formation and Cellular Localization of TDP-43 Aggregates in Amyotrophic Lateral Sclerosis. Mol Neurobiol 57, 1361–1373 (2020). https://doi.org/10.1007/s12035-019-01810-7

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Keywords

  • ALS
  • TDP-43
  • SUMO
  • Aggregation