Item Type: | Preprint |
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Title: | Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia |
Creators Name: | Tan, L.X., Oertel, F.C., Cheng, A., Cobigo, Y., Keihani, A., Bennett, D.J., Abdelhak, A., Montes, S.C., Chapman, M., Chen, R.Y., Cordano, C., Ward, M.E., Casaletto, K., Kramer, J.H., Rosen, H.J., Boxer, A., Miller, B.L., Green, A.J., Elahi, F.M. and Lakkaraju, A. |
Abstract: | Mutations in progranulin (GRN) cause frontotemporal dementia (GRN-FTD) due to deficiency of the pleiotropic protein progranulin. GRN-FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN-FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn(-/-) mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn(-/-) RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NFkB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation. |
Keywords: | Animals, Mice |
Source: | bioRxiv |
Publisher: | Cold Spring Harbor Laboratory Press |
Article Number: | 2024.05.29.595206 |
Date: | 1 June 2024 |
Official Publication: | https://doi.org/10.1101/2024.05.29.595206 |
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