Characterization of CHMP2Bintron5 mice, a model of ALS-FTD continuum

Background: Since the discovery of a gene involved in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), many studies focus on the idea of genetic and pathophysiological continuum between these two neurodegenerative diseases. Indeed, 50% of FTD patients also develop motor symptoms (1). Moreover, about 15% of ALS patients concomitantly develop FTD. Chmp2B was the first mutated gene identified in both FTD and ALS patients. Chmp2b encodes a protein involved in endocytic pathways, intraluminal vesicles formation, virus budding and cytokinesis. The main form of Chmp2B mutant, found in FTD patients, is called Chmp2Bintron5. This mutation leads to the cterminal truncation of 36 last amino acids (2). To date, the mechanisms leading to neuronal dysfunctions linked to Chmp2B mutant are poorly understood. Objective: Study the clinical and the physiopathological continuum between ALS and FTD using a novel mouse model, which expresses CHMP2Bintron5 mutant in neurons. Methods: Using complementary biochemical, histological and behavioural techniques we have characterized a newly generated transgenic mouse line expressing CHMP2Bintron5 mutant under control of the Thy1.2 promoter (3). Results: The CHMP2Bintron5 mice have decreased survival and show progressive neurodegenerative changes leading to motor and behavioural alterations. They show a strong expression of the mutant protein in neurons of the brain and the spinal cord, especially in the anterior cortex and in motor neurons. This expression is associated with a gliosis and the presence of P62, ubiquitin and Chmp2Bintron5-positive inclusions. The motor phenotype recapitulates several aspects of human ALS. Homozygous mutants exhibit severe and early locomotor impairments as attested by a decrease of rotarod performance and grip strength, and gait abnormalities at 2 months of age. These impairments appear from 15 months of age in hemizygous mice and develop toward a final paralysis associated with muscle denervation, as assessed by electromyography. We further show behavioral defects relevant for FTD such as stereotypies (repetitive rearing, excessive grooming), food intake abnormalities and anxiety decrease. Discussion: Here, we report the generation of a Transgenic line expressing a human ALS/FTD-causing mutation that reproduces part of the ALS-FTD symptoms. Our data provide robust in vivo evidence of neurodegenerative mechanisms driven by the expression of the CHMP2Bintron5 mutant. Next, compared with data obtain in ALS or FTD mice models, our data allowed us to identify common or specific mechanisms in the two diseases