Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction
| Autor: | Katrianne Bethia Koh, Jerry Liu, Ira Agrawal, Jer-Cherng Chang, Emma Sanford, Greg Tucker-Kellogg, David H. Gutmann, Audrey Yi Tyan Peng, Shuo-Chien Ling, Jodie Hon Kiu Man, Ashley J. Pinter, Qi Xuan Cheryl Phua, Peiyan Wong, Wan Yun Ho, Yi-Chun Yen |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Neuromuscular Junction Biology Neuromuscular junction Mice mental disorders Motor system medicine Animals Amyotrophic lateral sclerosis Cell Proliferation Mice Knockout Motor Neurons Denervation Multidisciplinary Microglia Amyotrophic Lateral Sclerosis nutritional and metabolic diseases Biological Sciences Spinal cord medicine.disease nervous system diseases DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal Oligodendroglia Phenotype medicine.anatomical_structure Astrocytes Female Transcriptome Nucleus Neuroscience Gene Deletion Astrocyte |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2007806117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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