Home > Publications Database > Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. > print

001     163937
005     20240302115205.0
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024 7 _ |a 10.15252/embr.202153890
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024 7 _ |a pmid:35438230
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024 7 _ |a 1469-221X
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024 7 _ |a 1469-3178
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082 _ _ |a 570
100 1 _ |a Riemenschneider, Henrick
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245 _ _ |a Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.
260 _ _ |a Hoboken, NJ [u.a.]
|c 2022
|b Wiley
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500 _ _ |a (CC BY)
520 _ _ |a Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa ('TDP-25') accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALS-causing TDP-43 mutations. These findings support a patho-physiological relevance of proteasome dysfunction in ALS/FTD.
536 _ _ |a 352 - Disease Mechanisms (POF4-352)
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650 _ 7 |a ALS
|2 Other
650 _ 7 |a TDP-43
|2 Other
650 _ 7 |a neurodegeneration
|2 Other
650 _ 7 |a phase separation
|2 Other
650 _ 7 |a proteasome
|2 Other
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: genetics
|2 MeSH
650 _ 2 |a DNA-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: genetics
|2 MeSH
650 _ 2 |a Frontotemporal Dementia: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Inclusion Bodies: metabolism
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Peptide Fragments: genetics
|2 MeSH
650 _ 2 |a Peptide Fragments: metabolism
|2 MeSH
650 _ 2 |a Proteasome Endopeptidase Complex: metabolism
|2 MeSH
700 1 _ |a Guo, Qiang
|0 0000-0003-3520-5439
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700 1 _ |a Bader, Jakob
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700 1 _ |a Frottin, Frédéric
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700 1 _ |a Farny, Daniel
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700 1 _ |a Kleinberger, Gernot
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700 1 _ |a Haass, Christian
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700 1 _ |a Mann, Matthias
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700 1 _ |a Hartl, F Ulrich
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700 1 _ |a Baumeister, Wolfgang
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700 1 _ |a Hipp, Mark S
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700 1 _ |a Meissner, Felix
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700 1 _ |a Fernández-Busnadiego, Rubén
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700 1 _ |a Edbauer, Dieter
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773 _ _ |a 10.15252/embr.202153890
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856 4 _ |y OpenAccess
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