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DPR-MODELS Report Summary

Project ID: 617198
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - DPR-MODELS (C9orf72 repeat expansion in FTD/ALS - from mechanisms to therapeutic approaches)

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases with overlapping genetics and pathology. The most common known cause is expansion of a GGGGCC repeat in the first intron of the gene C9orf72. In 2013, we discovered that the repeat region is translated into aggregating dipeptide-repeat (DPR) proteins despite its intronic localization and lack of an ATG start codon. Unconventional translation of sense and antisense transcripts in all reading frames results in poly-GA, -GP, -GR, -PR and –PA expression. DPR aggregates outnumber the previously identified TDP-43 inclusions in the hippocampus, cortex and cerebellum. In this project we characterize this unusual pathomechanism in detail to elucidate the mechanisms of translation, toxicity, aggregation and clearance of DPR proteins.

Up to now, the key discoveries of the projects are:

1. We established cellular models for individual DPR protein expression using synthetic genes that show preferential neurotoxicity of poly-GA and poly-PR. To identify mechanisms of toxicity we identified neuronal proteins interacting with DPR proteins by mass spectrometry. For example, poly-GA aggregates sequester the proteasome and Unc119, which contributes to apoptosis. We also use a repeat expressing model for screening of compound libraries to inhibit DPR expression pharmacologically.

2. Using our cellular models we discovered cell-to-cell transmission of the hydrophobic DPR proteins, which supports the feasibility of DPR-directed immunotherapy for C9orf72 patients. Moreover, our in depth neuropathological analysis of the different DPR species in FTLD and ALS patients supports a role of cerebellar DPR pathology in the development of FTLD through non-cell autonomous effects.

3. We generated three mouse lines expressing different DPR proteins. Moreover, our antibody toolbox has helped to characterize several C9orf72 mouse models from other groups. At 6 months our poly-GA expressing mice show motor deficits without overt neuron loss suggest poly-GA aggregates disturb neuronal function even prior to cell death. These mice will now be used for testing therapeutic strategies such as immunotherapy.

In the first 30 months we made significant progress in the understanding and modeling C9orf72 disease in vitro and in vivo. We are now using these tools to develop strategies to inhibit expression, aggregation and toxicity of DPR proteins and use immunotherapy to remove DPR proteins from the brain. Alone or in combination these approaches may help to cure or prevent the most common genetic form of ALS and FTD.

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