Selective Spatiotemporal Vulnerability of Central Nervous System Neurons to Pathologic TAR DNA-Binding Protein 43 in Aged Transgenic Mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy because of loss of upper and lower motor neurons. Histopathologically, most patients with ALS have abnormal cytoplasmic accumulation and aggregation of the nuclear RNA-regulating protein TAR DNA-binding protein 43 (TDP-43). Pathogenic mutations in the TARDBP gene that encode TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43 mice), presenting with early-onset motor deficits in adolescent animals. Here, we analyzed aged iTDP-43 mice, focusing on the spatiotemporal profile and progression of neurodegeneration in upper and lower motor neurons. Magnetic resonance imaging and histologic analysis revealed a differential loss of upper motor neurons in a hierarchical order as iTDP-43 mice aged. Furthermore, we report progressive gait problems, profound motor deficits, and muscle atrophy in aged iTDP-43 mice. Despite these deficits and TDP-43 pathologic disorders in lower motor neurons, stereological analysis did not show cell loss in spinal cords. Taken together, neuronal populations in aging iTDP-43 mice show differential susceptibility to the expression of human TDP-43.

Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice

“…Transgene expression was not present in all ChAT positive motor neurons in transgenic embryos. This is consistent with other transgenic mouse lines that have pan-neuronal expression (van Hummel et al, 2018). This confirms that the phenotypes present in the Hb9 V5-PFN1 C71G transgenic mice are a direct result of the developmental and neonatal expression of the ALS-associated PFN1 mutant.…”

“…Another factor was the reduction of mouse numbers over time, due to the reduced survival of Hb9 V5-PFN1 C71G transgenic mice. Although young transgenic mice presented with motor deficits consistent with other ALS mouse models (Yang et al, 2016; van Hummel et al, 2018), the aged transgenic mice presented with a split motor phenotype which has not been previously reported. The split weight phenotype could be masking the motor phenotype in the low weight mice.…”

“…Each mouse was given five attempts and the highest peak force (N) exerted was recorded (Ittner et al, 2016). The hanging wire test was used as previously described (van Hummel et al, 2018). For this, mice completed two trials and the best performance was recorded.…”

Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity

“…Brains for stainings were processed in an Excelsior tissue processor (Thermo) and paraffin embedded, while brains from AAV-injected mice were sectioned to 50 μm with Vibratome and imaged on a Zeiss Axio Scan.Z1 fluorescence scanner; the number and intensity of mAG+ cells were analyzed by Fiji ImageJ (NIH). Quantification of fluorescence was performed as previously described (81,83).…”

Neurodegeneration and Motor Deficits in the Absence of Astrogliosis upon Transgenic Mutant TDP-43 Expression in Mature Mice

“…10 In addition, a selective vulnerability of upper motor neurons to pathologic TDP-43 A315T was further identified when aged iTDP-43 A315T mice were analyzed. 12 Both previous studies are in iTDP-43 A315T mice with constitutive transgene expression. In this report, the delayed expression of this human TDP-43 A315T is further characterized by transgene suppression through oral doxycycline treatment from gestation to weaning.…”