This thesis investigates protein-mediated pathomechanisms and biomarkers in two familial forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in cell culture and patient material. I focused on the ubiquitin-proteasome system (UPS), spreading-mechanisms and mitochondrial dysfunction. The most frequent genetic cause of FTD and ALS is a GGGGCC-repeat expansion mutation in the intronic region of C9orf72. Patients harbor hundreds of repeats that are bi-directionally

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... bed. Repeat-containing transcripts form nuclear RNA foci and are unconventionally translated in all reading frames into five dipeptide repeat (DPR) proteins (poly-GA, poly-GP, poly-GR, poly-PA and poly-PR). These DPR proteins coaggregate specifically in C9orf72 patient brains, but their pathogenic nature is still under intense debate. In C9orf72 FTD/ALS and other neurodegenerative diseases, dysfunction of the UPS has been discussed as cause or consequence of protein aggregation. To gain deeper insights into the ultrastructure of poly-GA aggregates, we conducted cryo-electron tomography in primary neurons. We found that poly-GA aggregates consist of densely packed twisted ribbons immobilizing numerous 26S proteasomes that are stalled in a rare transition state indicating an unsuccessful degradation attempt. I validated the colocalization of the proteasome with poly-GA and confirmed sequestration of the proteasome by biochemical fractionation. Altogether these results indicate that proteasomes are trapped in poly-GA aggregates and inhibit the UPS (Publication II). Cell-to-cell transmission of intracellular protein aggregates is emerging as a common feature in neurodegenerative diseases. As part of a study on transmission of DPR protein, I conducted co-culture experiments in primary neurons revealing that poly-GA is released and taken up by other neurons. Unexpectedly, I observed that overexpression of poly GA also induced RNA foci formation in C9orf72 fibroblasts suggesting a transcriptional feedback mechanism. Together thes [...]