Gel-like inclusions of C-terminal fragments of TDP-43 sequester and inhibit proteasomes in neurons

Riemenschneider, H.; Guo, Q.; Bader, J.; Frottin, F.; Farny, D.; Kleinberger, G.; Haass, C.; Mann, M.; Hartl, F. U.; Baumeister, W.; Hipp, M. S.; Meissner, F.; Fernandez-Busnadiego, R.; Edbauer, D.

doi:10.1101/2021.03.15.435268

bioRxiv · 10.1101/2021.03.15.435268

Gel-like inclusions of C-terminal fragments of TDP-43 sequester and inhibit proteasomes in neurons

Riemenschneider, H.·Guo, Q.·Bader, J.·Frottin, F.·Farny, D.·Kleinberger, G.·Haass, C.·Mann, M.·Hartl, F. U.·Baumeister, W.·Hipp, M. S.·Meissner, F.·Fernandez-Busnadiego, R.·Edbauer, D.

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Abstract

TDP-43 inclusions enriched in C-terminal fragments of ~25kDa ("TDP-25") are associated with neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we analyzed gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics and functional assays. TDP-25 inclusions are amorphous with gel-like biophysical properties and sequester proteasomes adopting exclusively substrate-processing conformations. This leads to proteostasis impairment, further enhanced by pathogenic mutations. These findings bolster the importance of proteasome dysfunction in ALS/FTD.

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Riemenschneider, H., Guo, Q., Bader, J., Frottin, F., Farny, D., Kleinberger, G., Haass, C., Mann, M., Hartl, F. U., Baumeister, W., Hipp, M. S., Meissner, F., Fernandez-Busnadiego, R., Edbauer, D.. 2021-03-16. Gel-like inclusions of C-terminal fragments of TDP-43 sequester and inhibit proteasomes in neurons. https://doi.org/10.1101/2021.03.15.435268

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