Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model
Year: 2026
Type: preprint
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G 4 C 2 ) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2α has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2α phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2α phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G 4 C 2 , where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.
Authors: Paulina Torres, Daniela Becerra, José I. Astorga, Matías Fuentealba, Grant Kauwe, Luis Gonzalez, Guillermo Diaz, Vania Morales, Vicente Valenzuela, Cameron Wehrfritz, Yani Y. Ngwala, Claudia Sepulveda-Quiñenao, Samah Shah, Joanna Bons, Leonard Petrucelli, Tara E. Tracy, Birgit Schilling, Claudio Hetz
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, Buck Institute for Research on Aging, New York Genome Center, Agencia Nacional de Investigación y Desarrollo, National Institutes of Health, Comisión Nacional de Investigación Científica y Tecnológica, Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias, U.S. Army Medical Research Acquisition Activity
Awards: G103627852, ROLE OF THE UNFOLDED PROTEIN RESPONSE (UPR) IN THE PROGRESSION OF BRAIN CANCER, CENTRO DE GEROCIENCIA SALUD MENTAL Y METABOLISMO (GERO), G4629423607, G511417034, UNCOVERING THE CONTRIBUTION OF CELL-TYPE-SPECIFIC ER PROTEOSTASIS NETWORKS TO PD PATHOGENESIS, DEFINING THE SIGNIFICANCE OF THE UNFOLDED PROTEIN RESPONSE (UPR) AS A THERAPEUTIC TARGET TO TREAT LIVER FIBROSIS, G8162482449, G883642430, G892262892
OpenAlex ID: W7202094034