Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Zhang, J., Velmeshev, D., Hashimoto, K., Huang, Y., Hofmann, J. W, Shi, X., Chen, J., Leidal, A. M, Dishart, J. G, Cahill, M. K, Kelley, K. W, Liddelow, S. A, Seeley, W. W, Miller, B. L, Walther, T. C, Farese, J., Taylor, J P., Ullian, E. M, Huang, B., Debnath, J., Wittmann, T., Kriegstein, A. R, & Huang, E. J Nature, 588(7838):459–465, August, 2020.
abstract   bibtex   
Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin(1,2). However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn(-/-) microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn(-/-) microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.
@ARTICLE{Zhang2020-dj,
  title    = "Neurotoxic microglia promote {TDP-43} proteinopathy in
              progranulin deficiency",
  author   = "Zhang, Jiasheng and Velmeshev, Dmitry and Hashimoto, Kei and
              Huang, Yu-Hsin and Hofmann, Jeffrey W and Shi, Xiaoyu and Chen,
              Jiapei and Leidal, Andrew M and Dishart, Julian G and Cahill,
              Michelle K and Kelley, Kevin W and Liddelow, Shane A and Seeley,
              William W and Miller, Bruce L and Walther, Tobias C and Farese,
              Jr, Robert V and Taylor, J Paul and Ullian, Erik M and Huang, Bo
              and Debnath, Jayanta and Wittmann, Torsten and Kriegstein, Arnold
              R and Huang, Eric J",
  abstract = "Aberrant aggregation of the RNA-binding protein TDP-43 in neurons
              is a hallmark of frontotemporal lobar degeneration caused by
              haploinsufficiency in the gene encoding progranulin(1,2).
              However, the mechanism leading to TDP-43 proteinopathy remains
              unclear. Here we use single-nucleus RNA sequencing to show that
              progranulin deficiency promotes microglial transition from a
              homeostatic to a disease-specific state that causes endolysosomal
              dysfunction and neurodegeneration in mice. These defects persist
              even when Grn(-/-) microglia are cultured ex vivo. In addition,
              single-nucleus RNA sequencing reveals selective loss of
              excitatory neurons at disease end-stage, which is characterized
              by prominent nuclear and cytoplasmic TDP-43 granules and nuclear
              pore defects. Remarkably, conditioned media from Grn(-/-)
              microglia are sufficient to promote TDP-43 granule formation,
              nuclear pore defects and cell death in excitatory neurons via the
              complement activation pathway. Consistent with these results,
              deletion of the genes encoding C1qa and C3 mitigates microglial
              toxicity and rescues TDP-43 proteinopathy and neurodegeneration.
              These results uncover previously unappreciated contributions of
              chronic microglial toxicity to TDP-43 proteinopathy during
              neurodegeneration.",
  journal  = "Nature",
  volume   =  588,
  number   =  7838,
  pages    = "459--465",
  month    =  aug,
  year     =  2020,
  language = "en"
}
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