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.; Abdelhak, A.; Montes, S. C.; Chapman, M.; Chen, R.; Cordano, C.; Ward, M.; Casaletto, K.; Kramer, J.; Rosen, H. H.; Boxer, A. L.; Miller, B. L.; Green, A.; Elahi, F.; Lakkaraju, A.
Show 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 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.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders. 97%
- Identification of Chlamydia pneumoniae and NLRP3 inflammasome activation in Alzheimer's disease retina 96%
- Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration 96%
Similar papers in this journal
- Retinoic acid signaling mediates peripheral cone photoreceptor survival in a mouse model of retina degeneration 96%
- Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms 95%
- Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons 95%
Similar papers in this journal
- Inflammation Of The Retinal Pigment Epithelium Drives Early-Onset Photoreceptor Degeneration In Mertk-Associated Retinitis Pigmentosa 97%
- Inhibiting retinoic acid mitigates vision loss in a mouse model of retinal degeneration 95%
- Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration. 94%
Similar papers in this journal
Similar papers in this journal
- Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder 95%
- Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimers mouse model 94%
- Reversal of neuronal tau pathology, metabolic dysfunction, and electrophysiological defects via adiponectin pathway dependent AMPK activation. 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.