Altered astrocytic expression of TDP-43 does not influence motor neuron survival

Amanda M. Haidet-Phillips, Sarah K. Gross, Timothy Williams, Alisha Tuteja, Alex Sherman, Myungsung Ko, Yun H. Jeong, Philip C. Wong, Nicholas J. Maragakis

Research output: Contribution to journalArticlepeer-review

Abstract

The role of glia as a contributing factor to motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) is becoming increasingly appreciated. However, most studies implicating astrocytes have focused solely on models of ALS caused by superoxide dismutase 1 (SOD1) mutations. The goal of our study was to determine whether astrocytes contribute to wild-type MN death in the case of ALS caused by mutations in tar-DNA binding protein 43 (TDP-43). Since it is currently unknown how TDP-43 mutations cause disease, we derived astrocytes for study from both gain and loss of function mouse models of TDP-43. Astrocytes overexpressing mutant TDP-43A315T as well as astrocytes lacking TDP-43 were morphologically indistinguishable from wild-type astrocytes in vitro. Furthermore, astrocytes with these TDP-43 alterations did not cause the death of wild-type MNs in co-culture. To investigate the in vivo effects of TDP-43 alterations in astrocytes, glial-restricted precursors were transplanted to the wild-type rat spinal cord where they differentiated into astrocytes and interacted with host MNs. Astrocytes with TDP-43 alterations did not cause host wild-type MN damage although they were capable of engrafting and interacting with host MNs with the same efficiency as wild-type astrocytes. These data indicate that astrocytes do not adopt the same toxic phenotype as mutant SOD1 astrocytes when TDP-43 is mutated or expression levels are modified. Our study reinforces the heterogeneity in ALS disease mechanisms and highlights the potential for future screening subsets of ALS patients prior to treatment with cell type-directed therapies.

Original languageEnglish (US)
Pages (from-to)250-259
Number of pages10
JournalExperimental Neurology
Volume250
DOIs
StatePublished - Dec 2013

Keywords

  • ALS
  • Amyotrophic lateral sclerosis
  • Cell autonomy
  • Glia
  • Stem cells

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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