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

Maurel, Cindy; Chami, Anna A.; Thépault, Rose Anne; Marouillat, Sylviane; Blasco, Hélène; Corcia, Philippe; Andres, Christian R.; Vourc’h, Patrick

doi:10.1007/s12035-019-01810-7

Cited by 23 publications

(29 citation statements)

References 42 publications

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“…However, our results demonstrated that SUMOylation of TDP-43 protein itself is also important to regulate its nucleocytoplasmic shuttling because the SUMO-mutant TDP-43 K136R was less e ciently distributed in the cytoplasm upon induced deSUMOylation compared to the wild-type protein. Our observation that TDP-43 SUMO-modi cation regulates its sub-cellular distribution is supported also by the recent nding that the mutant GFP-TDP-43 K136R, when over-expressed to promote its self-assembly, is no longer able to form aggregates in the cytoplasm as the wild-type protein, but only in the nucleus [23].…”

Section: Discussionsupporting

confidence: 79%

“…Among the PTM described for TDP-43, including C-terminal cleavage, phosphorylation, ubiquitination and acetylation, SUMOylation has been only recently investigated [5,57]. TDP-43 was reported to be modi ed by SUMO-1 in murine tissues and human experimental TDP-43 cell models [22,23] and preliminary data already indicated that cytotoxic stress in HeLa cells was able to up-regulate protein SUMOylation, including that of TDP-43 [20].…”

Section: Discussionmentioning

confidence: 99%

“…TDP-43 was also identi ed as a physiological SUMO-1 target in murine testis [22] and brain [23]. Recently, is has been demonstrated that the chemical inhibition of the SUMOylation pathway by anacardic acid reduces the formation of TDP-43 aggregates upon over-expression of GFP-TDP-43 in murine NSC-34 cells [23]. However, whether SUMOylation regulates TDP-43 biological activities and participates in triggering pathological TDP-43 mislocalization and aggregation is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

Maraschi

Gumina

Dragotto

et al. 2021

Preprint

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The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106–110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

Maraschi

Gumina

Dragotto

et al. 2021

Preprint

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“…One possibility is to target the enzymes responsible for the PTMs driving this transition. For example, inhibition of CK-1d responsible for TDP-43 phosphorylation (Martínez-Gonzá lez et al, 2020), inhibition of TDP-43 SUMOylation by anacardic acid (Maurel et al, 2020), or increase TDP-43 acetylation by activation of HSF1 (Wang et al, 2017) revert its aggregation, while maintaining its nuclear physiological localization in models for ALS. Similarly, inhibition of PARP-1/2, responsible for polyADP-ribosylation of TDP-43, by small molecules blocks the formation of cytoplasmic aggregates (McGurk et al, 2018).…”

Section: Emerging Therapeutics Targeting Llps-related Mechanismsmentioning

confidence: 99%

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

et al. 2020

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“…SUMO-2/3 was predominantly colocalized with TDP-43 primarily in nuclear inclusions [ 68 ]. Maurel et al (2020) identified a unique consensus site for SUMOylation at lysine-136 of TDP-43 [ 69 ]. They further show that replacement of this residue with an arginine altered the intracellular localization of TDP-43 aggregates from the cytoplasm to the nucleus, indicating that SUMOylation of this residue is critical to TDP-43 cytoplasmic localization [ 69 ].…”

Section: Pathogenic Mechanisms Of Tdp-43 In Cell and Animal Modelsmentioning

confidence: 99%

Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

Wood

Gurfinkel

Polain

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.

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

Cited by 23 publications

References 42 publications

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

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