Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

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.; Lakkaraju, A.

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

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Item Type:	Preprint
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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