Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.

Abstract

Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43∆NLS in these 'regulatable NLS' (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43∆NLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery.

• Authors: Adam K Walker, Krista J Spiller, Guanghui Ge, Allen Zheng, Yan Xu, Melissa Zhou, Kalyan Tripathy, Linda K Kwong, John Q Trojanowski, Virginia M-Y Lee
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 130 Issue 5 Pg. 643-60 (Nov 2015) ISSN: 1432-0533 [Electronic] Germany
• PMID: 26197969 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• TARDBP protein, human
• Doxycycline

Topics

• Amyotrophic Lateral Sclerosis (pathology, physiopathology)
• Animals
• Atrophy
• Brain (metabolism, pathology)
• Cell Nucleus (metabolism, pathology)
• Cytoplasm (metabolism, pathology)
• DNA-Binding Proteins (genetics, metabolism)
• Disease Models, Animal
• Doxycycline
• Female
• Frontotemporal Lobar Degeneration (pathology, physiopathology)
• Humans
• Male
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Movement Disorders (pathology, physiopathology)
• Muscle, Skeletal (innervation)
• Random Allocation
• Recovery of Function (physiology)
• Spinal Cord (metabolism, pathology)