Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains

Seyfried, Nicholas T.; Gozal, Yair M.; Dammer, Eric B.; Xia, Qiangwei; Duong, Duc M.; Cheng, Dongmei; Lah, James J.; Levey, Aĺlan I.; Peng, Junmin

doi:10.1074/mcp.m800390-mcp200

Cited by 102 publications

(129 citation statements)

References 72 publications

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“…To some extent, accumulation of substrates marked by polyUb for delivery to one system may be redirected to the other system to accommodate the burden of proteolysis. (51). On the other hand, it is also possible that Lys 63 chains are the dominant signal in sorting of substrates with mixed linkages, and the role of other linkages is passive.…”

Section: Discussionmentioning

confidence: 99%

Polyubiquitin Linkage Profiles in Three Models of Proteolytic Stress Suggest the Etiology of Alzheimer Disease

Dammer

Na²,

Xu³

et al. 2011

Journal of Biological Chemistry

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149

137

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Section: Discussionmentioning

confidence: 99%

Polyubiquitin Linkage Profiles in Three Models of Proteolytic Stress Suggest the Etiology of Alzheimer Disease

Dammer

Na²,

Xu³

et al. 2011

Journal of Biological Chemistry

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149

137

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“…First, several observations support a direct role for SUMOylation in diverse pathogenic mechanisms involved in ALS, such as response to hypoxia, oxidative stress, glutamate excitotoxicity, and proteasome impairment. Next, SOD1 protein and transactive response DNA-binding protein 43 (TDP-43) are targets of SUMO modifications [13,14,25]. Finally, we showed here that SUMO is present in aggregates in motor neuronal cells expressing ALS-related SOD1 mutants.…”

Section: Discussionmentioning

confidence: 67%

Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

Dangoumau

Marouillat

Gaillard³

et al. 2015

Neurodegener Dis

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons. Mutations in the SOD1 gene encoding the superoxide dismutase 1 are present in 15% of familial ALS cases and in 2% of sporadic cases. These mutations are associated with the formation of SOD1-positive aggregates. The mechanisms of aggregation remain unknown, but posttranslational modifications of SOD1 may be involved. Here, we report that NSC-34 motor neuronal cells expressing mutant SOD1 contained aggregates positive for small ubiquitin modifier-1 (SUMO-1), and in parallel a reduced level of free SUMO-1. CLEM (correlative light and electron microscopy) analysis showed nonorganized cytosolic aggregates for all mutations tested (SOD1^A4V, SOD1^V31A, and SOD1^G93C). We next show that preventing the SUMOylation of mutant SOD1 by the substitution of lysine 75, the SUMOylation site of SOD1, significantly reduces the number of motor neuronal cells with aggregates. These results support the need for further research on the SUMOylation pathways, which may be a potential therapeutic target in ALS.

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“…Under the microscope, the researchers saw that most of the TDP-43 transgene remained nuclear, but when it moved into the cytoplasm the cells displayed swelling, nuclear fragmentation, and cell death. Both have been linked to toxicity [9,15]. When Li and colleagues expressed solely the carboxyl-terminal fragment in their flies, they found no neurotoxicity, supporting evidence that the amino terminus contributes to pathogenesis.…”

Section: Research Brief: There Is a Fly In My Tdp-43 Researchmentioning

confidence: 82%

TDP-43 Models Coverage

2010

JAD

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There is a new mouse in the laboratory for the study of amyotrophic lateral sclerosis (ALS). And there will soon be more: mice carrying a mutant version of human TAR DNA binding protein 43 (TDP-43) will likely herald a veritable herd of mice with various TDP-43 mutations. Robert Baloh and colleagues at Washington University in St. Louis, Missouri, reported on the first published transgenic model of TDP-43 proteinopathy, describing a mouse that shows features of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), another TDP-43 proteinopathy that sometimes co-presents with ALS [1]. Surprisingly, the mouse lacks one common feature of human disease: although there are ubiquitinated protein inclusions in the animal's neurons, TDP-43 is not a component of the aggregates. This could indicate that TDP-43 aggregates are not central to disease -or simply suggest that the model is a poor facsimile of human disease.John Trojanowski of the University of Pennsylvania in Philadelphia, who was not involved in the current research, applauded the publication. "This will energize the field," he said. Several laboratories are working on their own TDP-43 mouse models; Trojanowski joked good-naturedly that he was "crushed" to see Baloh's group make it into print publication first.However, researchers warned against overinterpreting early results, particularly since the current publication lacked control mice overexpressing wild-type human TDP-43. "We have to be incredibly cautious as far as what these results mean," said Leonard Petrucelli of the Mayo Clinic in Jacksonville, Florida, who also was not a participant in the PNAS paper. "I think it is a bit of a stretch to say that it is an ALS model per

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Multiplex SILAC Analysis of a Cellular TDP-43 Proteinopathy Model Reveals Protein Inclusions Associated with SUMOylation and Diverse Polyubiquitin Chains

Cited by 102 publications

References 72 publications

Polyubiquitin Linkage Profiles in Three Models of Proteolytic Stress Suggest the Etiology of Alzheimer Disease

Polyubiquitin Linkage Profiles in Three Models of Proteolytic Stress Suggest the Etiology of Alzheimer Disease

Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

TDP-43 Models Coverage

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