Frontiers in Cellular Neuroscience (Apr 2023)
C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice
- Maria-Belen Lopez-Herdoiza,
- Stephanie Bauché,
- Baptiste Wilmet,
- Caroline Le Duigou,
- Delphine Roussel,
- Magali Frah,
- Jonas Béal,
- Gabin Devely,
- Susana Boluda,
- Petra Frick,
- Delphine Bouteiller,
- Sébastien Dussaud,
- Pierre Guillabert,
- Carine Dalle,
- Magali Dumont,
- Agnes Camuzat,
- Dario Saracino,
- Mathieu Barbier,
- Gaelle Bruneteau,
- Phillippe Ravassard,
- Manuela Neumann,
- Manuela Neumann,
- Sophie Nicole,
- Isabelle Le Ber,
- Alexis Brice,
- Morwena Latouche,
- Morwena Latouche
Affiliations
- Maria-Belen Lopez-Herdoiza
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Stephanie Bauché
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Baptiste Wilmet
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Caroline Le Duigou
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Delphine Roussel
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Magali Frah
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Jonas Béal
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Gabin Devely
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Susana Boluda
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Petra Frick
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Delphine Bouteiller
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Sébastien Dussaud
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Pierre Guillabert
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Carine Dalle
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Magali Dumont
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Agnes Camuzat
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Dario Saracino
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Mathieu Barbier
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Gaelle Bruneteau
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Phillippe Ravassard
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Manuela Neumann
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Manuela Neumann
- Department of Neuropathology, Tübingen University Hospital, Tübingen, Germany
- Sophie Nicole
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Isabelle Le Ber
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Alexis Brice
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Morwena Latouche
- Institut du Cerveau–Paris Brain Institute–ICM, Inserm, CNRS, Paris, France
- Morwena Latouche
- EPHE, Neurogenetics Team, PSL Research University, Paris, France
- DOI
- https://doi.org/10.3389/fncel.2023.1155929
- Journal volume & issue
-
Vol. 17
Abstract
The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS.
Keywords
- TDP-43
- C9ORF72
- FTD (frontotemporal dementia)
- ALS (amyotrophic lateral sclerosis)
- autophagy/lysosomal pathway
