| Autor: |
Tan LX, Oertel FC, Cheng A, Cobigo Y, Keihani A, Bennett DJ, Abdelhak A, Montes SC, Chapman M, Chen RY, Cordano C, Ward ME, Casaletto K, Kramer JH, Rosen HJ, Boxer A, Miller BL, Green AJ, Elahi FM, Lakkaraju A |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 01. Date of Electronic Publication: 2024 Jun 01. |
| DOI: |
10.1101/2024.05.29.595206 |
| Abstrakt: |
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 NF-kB-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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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