Journal Article

Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats

Tong, Jianbin, Huang, Cao, Bi, Fangfang, Xia, Xu-Gang, Zhou, Hongxia

2012

Overview

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. All of these rats developed progressive paralysis reminiscent of ALS when the transgene was switched on. Rats expressing mutant TDP-43 in motor neurons alone lost more spinal motor neurons than rats expressing the disease gene in varying neurons and muscle cells, although these rats all developed remarkable denervation atrophy of skeletal muscles. Intriguingly, progression of the disease was halted after transgene expression was switched off; in rats with limited loss of motor neurons, we observed a dramatic recovery of motor function, but in rats with profound loss of motor neurons, we only observed a moderate recovery of motor function. Our finding suggests that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that motor neuron degeneration is partially reversible, at least in mutant TDP-43 transgenic rats.

• Publisher: American Society for Clinical Investigation
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - etiology / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - pathology / Amyotrophic Lateral Sclerosis - physiopathology / Animals / Base Sequence / Biomedical research / Dementia / Denervation / Disease / Disease Models, Animal / Disease Progression / DNA binding proteins / DNA Primers - genetics / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Doxycycline - pharmacology / Gene mutations / Genes / Genetic aspects / Health aspects / Humans / Motor Neurons - drug effects / Motor Neurons - pathology / Motor Neurons - physiology / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Nerve Degeneration - drug therapy / Nerve Degeneration - genetics / Nerve Degeneration - physiopathology / Neurodegeneration / Neurons / Paralysis / Physiological aspects / Rats / Rats, Transgenic / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Risk factors / Spinal cord / TDP-43 Proteinopathies - drug therapy / TDP-43 Proteinopathies - genetics / TDP-43 Proteinopathies - pathology / TDP-43 Proteinopathies - physiopathology / Transgenic animals