Wobbler mice modeling motor neuron disease display elevated transactive response DNA binding protein

Abstract Wobbler mice model motor neuron disease with a substantial decline in motor neurons. TDP-43 is a nucleic acid binding protein that accumulates, along with ubiquitin, in the cytoplasm of amyotrophic lateral sclerosis (ALS) motor neurons. Recently, it was reported that Cu/Zn superoxide dismutase type 1 (SOD1) familial amyotrophic lateral sclerosis (fALS) model mice do not mimic the TDP-43 changes seen in sporadic ALS, although they share a large number of other properties with the human disorder. We examined ubiquitin inclusions and TDP-43 expression in wobbler mice. TDP-43 mRNA, measured by quantitative reverse transcription–coupled PCR, was elevated in the wobbler spinal cord. Immunohistochemistry revealed intracellular ubiquitin inclusions and abnormal distribution of TDP-43 into the cytoplasm in wobblers similar to the staining reported in ALS. Finally, nuclear and cytoplasmic fractions, examined by Western immunoblotting, confirmed a delocalization of TDP-43 in the neurodegenerative wobbler. These observations indicate that wobbler mice, which suffer motor neuron loss at 21 days, undergo TDP-43 and ubiquitin changes characteristic of sporadic ALS.