Structural Insights Into TDP-43 and Effects of Post-translational Modifications

François‐Moutal, Liberty; Perez‐Miller, Samantha; Scott, David D.; Miranda, Victor G.; Mollasalehi, Niloufar; Khanna, May

doi:10.3389/fnmol.2019.00301

Cited by 115 publications

(84 citation statements)

References 198 publications

(331 reference statements)

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“…Similarly to SOD1, cysteine residues are candidates for the mediation of TDP-43 aggregation, although the mechanisms are still not completely explained [ 118 ]. TDP-43 has six cysteine residues, four located in RNA recognition motifs (Cys 173, 175, 198, and 244) and two in the N-terminal domain (Cys 39 and 50) [ 119 ], with no mutations found so far in ALS [ 104 ]. In fact, oxidation of cysteine residues in the RNA recognition motifs was shown to decrease protein solubility and lead to the formation of intra- and intermolecular disulfide bridges [ 120 , 121 ].…”

Section: Evidence On the Involvement Of Oxidative Stress In Alsmentioning

confidence: 99%

Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Cunha‐Oliveira

Montezinho

Mendes

et al. 2020

Oxidative Medicine and Cellular Longevity

118

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Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

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Section: Evidence On the Involvement Of Oxidative Stress In Alsmentioning

confidence: 99%

Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Cunha‐Oliveira

Montezinho

Mendes

et al. 2020

Oxidative Medicine and Cellular Longevity

118

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“…Unfolding of the protein was necessary to expose the import signals, which are otherwise hidden in the correctly folded protein. There are several hypotheses in this regard involving Hsp60 and Hsp70 [ 53 ], but the exact mechanism remains unresolved ( Figure 1 A).…”

Section: Physiological Roles Of Mitochondrial Tdp-43mentioning

confidence: 99%

Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Lucini

Braun

2021

Biomedicines

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In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

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“…PTM serve to regulate protein activity and interaction with their partners and contribute to nely tune a variety of cellular processes in a spatio-temporal manner. 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%

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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Structural Insights Into TDP-43 and Effects of Post-translational Modifications

Cited by 115 publications

References 198 publications

Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

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