TY - JOUR
T1 - Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction
AU - Peng, Audrey Yi Tyan
AU - Agrawal, Ira
AU - Ho, Wan Yun
AU - Yen, Yi Chun
AU - Pinter, Ashley J.
AU - Liu, Jerry
AU - Phua, Qi Xuan Cheryl
AU - Koh, Katrianne Bethia
AU - Chang, Jer Cherng
AU - Sanford, Emma
AU - Man, Jodie Hon Kiu
AU - Wong, Peiyan
AU - Gutmann, David H.
AU - Tucker-Kellogg, Greg
AU - Ling, Shuo Chien
N1 - Funding Information:
ACKNOWLEDGMENTS. The authors thank Dr. Edward Koo for sharing the confocal microscope; Dr. Fengwei Yu for sharing LacZ antibody; Xianiong Wang for assisting FACS; Jia Feng, Mandi See, Jiehao Wang, and Vivi Ding for their technical assistance; and all of the S.-C.L. laboratory members for support, discussion, and suggestions. The behavioral experiments were carried out at the Neuroscience Phenotyping Core Facility, which is supported by the National Medical Research Council–National University Health System Centre Grant–Neuroscience Phenotyping Core (NMRC/CG/M009/2017_NUH/ NUHS). This work was supported by grants to S.-C.L. from the Swee Liew-Wadsworth Endowment fund, National University of Singapore, National Medical Research Council (NMRC/OFIRG/0001/2016 and NMRC/OFIRG/0042/ 2017), and Ministry of Education (MOE2016-T2-1-024), Singapore.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/11/17
Y1 - 2020/11/17
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis (ALS) | TDP-43 | cell-autonomous | A1-reactive astrocytes | triglial dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85096365451&partnerID=8YFLogxK
U2 - 10.1073/pnas.2007806117
DO - 10.1073/pnas.2007806117
M3 - Article
C2 - 33127758
AN - SCOPUS:85096365451
SN - 0027-8424
VL - 117
SP - 29101
EP - 29112
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -