A frontotemporal dementia and motor neuron disease mouse model of tdp-43 proteinopathy
Date
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Motor neuron disease (MND), of which amyotrophic lateral sclerosis (ALS) is one example is a neurological disorder that involves the progressive loss of motor neurons. The death of these motor neurons leads to a loss of voluntary muscle control that can affect speaking, walking, breathing, and swallowing leading eventually to death. There is currently no cure for ALS therefore understanding mechanisms associated with the progression of this disease is crucial to developing a treatment. Transactive response DNA binding protein of 43kda (TDP-43) functions as a heterogeneous nuclear ribonucleoprotein (hnRNP) and is the major pathological protein in frontotemporal dementia (FTD, 50%) and sporadic ALS (95%). Mutations in TDP-43 account for ~5% of familial ALS cases. In a subset of cases with TDP-43 proteinopathy, patients clinically display both frontotemporal temporal dementia and motor deficits (FTD-MND). We have characterized an age-dependent decrease in motor function associated with pathological changes in mice selectively driving TDP-43 expression in the spinal cord and brain using a neuronal-specific (Prion) driver. Expression of a nuclear localization defective (NLS) TDP-43 mutant in spinal cord and brain showed severe motor deficit and significant changes in anxiety in 16-18 month old mice. Although there was a relatively late onset of symptoms compared to the human disease, that may be related to the low level of exogenous TDP-43 expression, these models may provide a better understanding of TDP-43 proteinopathies leading to the development of therapeutics to target these devastating diseases.