TY  - JOUR
AU  - Riemenschneider, Henrick
AU  - Guo, Qiang
AU  - Bader, Jakob
AU  - Frottin, Frédéric
AU  - Farny, Daniel
AU  - Kleinberger, Gernot
AU  - Haass, Christian
AU  - Mann, Matthias
AU  - Hartl, F Ulrich
AU  - Baumeister, Wolfgang
AU  - Hipp, Mark S
AU  - Meissner, Felix
AU  - Fernández-Busnadiego, Rubén
AU  - Edbauer, Dieter
TI  - Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.
JO  - EMBO reports
VL  - 23
IS  - 6
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00611
SP  - e53890
PY  - 2022
N1  - (CC BY)
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: metabolism
KW  - Humans
KW  - Inclusion Bodies: metabolism
KW  - Neurons: metabolism
KW  - Peptide Fragments: genetics
KW  - Peptide Fragments: metabolism
KW  - Proteasome Endopeptidase Complex: metabolism
KW  - ALS (Other)
KW  - TDP-43 (Other)
KW  - neurodegeneration (Other)
KW  - phase separation (Other)
KW  - proteasome (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9171420
C6  - pmid:35438230
DO  - DOI:10.15252/embr.202153890
UR  - https://pub.dzne.de/record/163937
ER  -