Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons producing muscle denervation, motor impairments, and brain atrophy. Deposition of insoluble cytosolic inclusions of Transactive Response (TAR)-DNA binding protein 43kDA (TDP-43) correlates with ALS-related pathology in affected tissues. To study the progression of ALS phenotypes and establish a model for testing therapeutic interventions, PsychoGenics characterized the Dox-regulatable TDP-43 (ΔNLS) mouse model of ALS1. This model shows increased neurofilament light chain (NF-L) levels, progressive motor deficits, overexpression of cytoplasmic TDP-43, and changes in compound muscle action potential (CMAP) responses.
NF-L Levels Are Elevated in Plasma and CSF of TDP-43 ∆NLS Mice
Plasma and CSF NF-L concentrations are elevated in 10-week-old ∆NLS mice following cessation of Dox treatment at 5 weeks of age. NF-L levels were measured by IMOA Quanterix technology.
Progression of Symptoms in TDP-43 ΔNLS Mice
Broad health and behavioral outcomes in tTA and ∆NLS mice following removal of Dox-containing chow. (A) Steady decline in body weight in ∆NLS mice. (B) Increased tremor and (C) clasping in ∆NLS mice starting at 2 weeks following removal of Dox. (D) Decreased survival of ∆NLS mice compared to tTA mice.
Neuromuscular Deficits in TDP-43 ∆NLS Mice as Assessed by EMG
Compound muscle action potential (CMAP) responses in gastrocnemius muscle as recorded via EMG in tTA and ∆NLS mice, following removal of Dox-containing chow. Note deficits in measured parameters appear by 5 weeks following removal of Dox diet. (A) CMAP response latency is increased, (B) CMAP response amplitude is decreased in ∆NLS mice compared to tTA mice. (C) Neuromuscular conduction velocity, a measure incorporating both nerve conduction velocity and latency at neuromuscular junction, is decreased
TDP-43 Sub-cellular Distribution
Total TDP-43 is greater in ∆NLS mice compared to tTA mice. Nuclear TDP-43 signals are decreased in ∆NLS mice, as TDP-43 has localized to the cytoplasm.
Reference
1. Walker AK, Spiller KJ, Ge G, Zheng A, Xu Y, Zhou M, Tripathy K, Kwong LK, Trojanowski JQ, Lee VM. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol. 2015 Nov;130(5):643-660.