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

• Published in: Neuroscience 2009-01, Vol.158 (2), p.745-750
• Main Authors: Dennis, J.S, Citron, B.A
• Format: Article
• Language: English
• Subjects: amyotrophic lateral sclerosis; Animals; Biological and medical sciences; Cell Nucleus - metabolism; Cytoplasm - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - genetics; Medical sciences; Mice; Mice, Neurologic Mutants; Motor Neuron Disease - metabolism; Motor Neuron Disease - pathology; neurodegeneration; Neurology; RNA, Messenger - metabolism; spinal cord; Spinal Cord - pathology; TARDBP; TDP-43; ubiquitin; Ubiquitin - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.10.030

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.