Profiling the genes affected by pathogenic TDP-43 in astrocytes

J Neurochem. 2014 Jun;129(6):932-9. doi: 10.1111/jnc.12660. Epub 2014 Feb 9.

Abstract

Mutation in TAR DNA binding protein 43 (TDP-43) is a causative factor of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurodegeneration may not require the presence of pathogenic TDP-43 in all types of relevant cells. Rather, expression of pathogenic TDP-43 in neurons or astrocytes alone is sufficient to cause cell-autonomous or non-cell-autonomous neuron death in transgenic rats. How pathogenic TDP-43 in astrocytes causes non-cell-autonomous neuron death, however, is not clear. Here, we examined the effect of pathogenic TDP-43 on gene expression in astrocytes. Microarray assay revealed that pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Representative genes Lcn2 and chitinase-3-like protein 1 were markedly up-regulated in astrocytes from primary culture and intact transgenic rats. Furthermore, synthetic chitinase-3-like protein 1 induced neuron death in a dose-dependent manner. Our results suggest that TDP-43 pathogenesis is associated with the simultaneous induction of multiple neurotoxic genes in astrocytes, which may synergistically produce adverse effects on neuronal survival and contribute to non-cell-autonomous neuron death. Restricted expression of pathogenic TDP-43 in astrocytes causes non-cell-autonomous motor neuron death in transgenic rats. As revealed by microarray assay, pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Therefore, TDP-43 pathogenesis is associated with simultaneous induction of neurotoxic genes and repression of neurotrophic genes in astrocytes.

Keywords: Chi3L1; Lcn2; TDP-43; amyotrophic lateral sclerosis; astrocytes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Astrocytes / physiology*
  • Cell Death / physiology
  • Cell Survival / physiology
  • Chitinase-3-Like Protein 1
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Extracellular Matrix Proteins / biosynthesis
  • Extracellular Matrix Proteins / genetics
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Glycoproteins / biosynthesis
  • Glycoproteins / genetics
  • Microarray Analysis
  • Molecular Sequence Data
  • Mutation / physiology
  • Nerve Growth Factors / biosynthesis
  • Nerve Growth Factors / genetics
  • Neurons / physiology
  • Polymerase Chain Reaction
  • Primary Cell Culture
  • Rats
  • Rats, Transgenic

Substances

  • CHI3L1 protein, rat
  • Chitinase-3-Like Protein 1
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Nerve Growth Factors

Associated data

  • GENBANK/GSE42091