Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction

Audrey Yi Tyan Peng, Ira Agrawal, Wan Yun Ho, Yi Chun Yen, Ashley J. Pinter, Jerry Liu, Qi Xuan Cheryl Phua, Katrianne Bethia Koh, Jer Cherng Chang, Emma Sanford, Jodie Hon Kiu Man, Peiyan Wong, David H. Gutmann, Greg Tucker-Kellogg, Shuo Chien Ling

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP-43–deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43–deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.

Original languageEnglish
Pages (from-to)29101-29112
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Keywords

  • Amyotrophic lateral sclerosis (ALS) | TDP-43 | cell-autonomous | A1-reactive astrocytes | triglial dysfunction

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