A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Mutations in the chargedmultivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with amixed ALS-FTD syndrome. Tomodel this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5mutant in a neuron-specificmanner. Thesemice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reducedmuscle strength and decreasedmotor coordination. CHMP2Bintron5mice died due to generalized paralysis.When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size ofmotor endplates and by a decrease of sciatic nerve axons area. However, spinalmotor neurons cell bodies were preserved until death. In addition to themotor dysfunctions, CHMP2Bintron5mice progressively developed FTD-relevant behaviouralmodifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2Bintron5. As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis andmicrogliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2Bintron5 in areas involved inmotor and cognitive functions induces progressivemotor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.