Mar 13, 2014

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

Proceedings of the National Academy of Sciences of the United States of America
Chunxing YangZuoshang Xu

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 co...Continue Reading

Mentioned in this Paper

TARDBP gene
Pathogenic Aspects
Pathogenesis
Malignant Neoplasm of Spinal Cord
Aggregation
Astrocytes
Internal Pyramidal Layer of Cerebral Cortex
Nerve Degeneration
Neoplasm of Uncertain or Unknown Behavior of Spinal Cord
Motor Neurons

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