Cover Image for this issue: doi: 10.1111/jnc.12564.
Profiling the genes affected by pathogenic TDP-43 in astrocytes
Article first published online: 9 FEB 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 129, Issue 6, pages 932–939, June 2014
How to Cite
J. Neurochem. (2014) 129, 932–939.
- Issue published online: 11 JUN 2014
- Article first published online: 9 FEB 2014
- Accepted manuscript online: 22 JAN 2014 02:46AM EST
- Manuscript Accepted: 14 JAN 2014
- Manuscript Revised: 19 DEC 2013
- Manuscript Received: 17 AUG 2013
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke. Grant Numbers: NS073829, NS072113, NS084089
- amyotrophic lateral sclerosis;
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.