Abstract
In order to treat progressive paralysis in ALS patients, it is critical to develop a mouse that closely models human ALS in both pathology and also in the timing of these events. We have recently generated new TDP-43 bigenic mice (called rNLS8) with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (hTDP-43∆NLS) under the control of the NEFH promoter. Our previous studies characterized the pathology and disease course in young rNLS8 mice following induction of neuronal hTDP-43ΔNLS. We now seek to examine if the order and timing of pathologic events are changed in aged mice. We found that the expression of hTDP-43∆NLS in 12+ month old mice did not accelerate the appearance of neuromuscular abnormalities or motor neuron (MN) death in the lumbar spinal cord (SC), though disease progression was accelerated. However, following suppression of the transgene, important differences between young and aged rNLS8 mice emerged in functional motor recovery. We found that recovery was incomplete in aged mice relative to their younger treatment matched counterparts based on gross behavioral measures and physiological recordings from the animals’ gastrocnemius (GC) muscles, despite muscle reinnervation by surviving MNs. This is likely because the reinnervation most often only resulted in partial nerve and endplate connections and the muscle’s junctional folds were much more disorganized in aged rNLS8 mice. We believe that these studies will be an important basis for the future design and evaluation of therapies designed to slow denervation and promote re-innervation in adult ALS patients.
Highlights
Most patients who develop ALS are between 40 and 70 years old, with juvenile onset occurring only very rarely [20]
We found that expression of hTDP-43ΔNLS resulted in the accumulation of abundant insoluble, phosphorylated TDP-43 in brain and spinal cord, concomitant with nuclear clearance of endogenous mouse TDP-43 [32]
Aging accelerates progression but not the onset of motor neuron disease The major advantage of the newly described rNLS8 mouse line is that the hTDP-43ΔNLS transgene is inducible by removing doxycycline (Dox) from the animals’ diet and suppressed by the reintroduction of Dox
Summary
Most patients who develop ALS are between 40 and 70 years old, with juvenile onset occurring only very rarely [20]. The loss of muscle mass and accompanying degeneration of neuromuscular junctions (NMJs) is called sarcopenia and is a major cause of disability in the elderly [25]. The number of acetylcholine receptors per NMJ are significantly lower in old versus young animals [7], and nerve conduction velocities are significantly diminished [31]. Though the majority of changes have not yet occurred by the median age of ALS diagnosis (54–61 years old depending on the population), it is important to consider these ongoing processes, with regard to longterm disease management
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
