Functional recovery in new mouse models of ALS/FTLD after clearance of TDP-43 pathology

Cytoplasmic TDP-43 pathology in brain and spinal cord is the pathological hallmark of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, currently available mouse models of TDP-43 proteinopathies largely fail to recapitulate key pathological features of human disease including cytoplasmic phosphorylated TDP-43, insoluble TDP-43 accumulation, and down-regulation of endogenous nuclear TDP-43, combined with the progressive neuron loss and motor dysfunction leading to death seen in ALS. Furthermore, it remains unknown whether or not clearance of TDP-43 pathology would be beneficial following disease development, which is relevant due to the relatively late stage of disease at which ALS and FTLD-TDP are usually diagnosed in patients. We therefore developed new mouse lines with the human NEFH promoter driving doxycycline (Dox)-suppressible brain and spinal cord expression of cytoplasmically-localized human TDP-43 (hTDP-43ΔNLS). These mice show phosphorylated TDP-43 pathology in motor cortex, spinal cord and hippocampus as early as 1 week after induction of hTDP-43ΔNLS expression, and develop limb tremor accompanied by hindlimb clasping at 2–3 weeks, along with a progressive decline in motor task performance. Brain and muscle atrophy begins at 4 weeks, and spinal cord motor neuron loss is detected at 6 weeks, with gradual weight loss leading to disease endstage at a median of 10.3 weeks. In order to delineate the contribution of TDP-43 pathology to disease progression, we used Dox to suppress hTDP-43ΔNLS expression after 6 weeks, when significant pathology is seen and neurodegeneration has occurred. Remarkably, TDP-43 pathology was rapidly cleared, nuclear TDP-43 returned and neuron loss was halted, allowing muscle reinnervation, motor task improvement and dramatic lifespan extension. Clearance of TDP-43 pathology is therefore beneficial even at late disease stages, indicating that targeting cytoplasmic TDP-43 is a worthy avenue for therapeutic development in ALS and FTLD-TDP.2 page(s