Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

“…Both TDP‐43 gain and loss of function have been proposed as possible crucial mechanisms in the pathogenesis of ALS, a devastating incurable neurodegenerative disorder, and both reduced TDP‐43 expression and TDP‐43 overexpression have detrimental effects in mice (Arnold et al , 2013; Yang et al , 2014). …”

“…Thus, the main approach to studying LOF, by using null mice, has been hampered because TDP‐43 knockout (KO) causes very early embryonic lethality, and heterozygous mice have normal levels of TDP‐43 due to autoregulation (Kraemer et al , 2010; Sephton et al , 2010; Wu et al , 2010; Ricketts et al , 2014). However, conditional KO strategies and downregulation of TDP‐43 via siRNA suggest that acute TDP‐43 loss of function could lead to neurodegeneration (Chiang et al , 2010; Wu et al , 2012; Iguchi et al , 2013; Yang et al , 2014). …”

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

“…Absence of TDP43 is lethal (25), and TDP43 knockdown recapitulates motor neuron loss in animal models (26). In addition, nuclear clearing of TDP43 is characteristic of ALS (27), and TDP43 overexpression triggers a reduction in endogenous (en)-TDP43 through autoregulation (15,28), suggesting that TDP43 overexpression may cause toxicity through a paradoxical reduction in en-TDP43.…”

An ultra-fast and scalable quantification pipeline for transposable elements from next generation sequencing data

“…It has been reported that loss of TDP-43 function causes ALS. 7,36 To measure scalability with the dataset. we also ran TEtranscripts to compare running time of both methods.…”