Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in...

Area of Science:

• Neuroscience
• Genetics
• Ophthalmology

Background:

• Mutations in progranulin (GRN) cause frontotemporal dementia (FTD) linked to protein deficiency.
• GRN-FTD involves diverse pathologies like lysosome dysfunction, microgliosis, and neuroinflammation, but the exact disease mechanism is unclear.

Purpose of the Study:

• To investigate the role of progranulin in retinal integrity and its connection to frontotemporal dementia.
• To elucidate the molecular mechanisms underlying progranulin deficiency-induced retinal dysfunction and neuroinflammation.

Main Methods:

• Non-invasive retinal imaging in GRN-FTD patients and Grn knockout mice.
• Super-resolution live imaging and transcriptomic analysis of retinal pigment epithelium (RPE) mitochondria.
• Investigated the role of mitochondrial fission protein 1 (MTFP1) and complement signaling (C3aR).

Main Results:

• Retinal imaging revealed photoreceptor and RPE deficits in GRN-FTD patients correlating with cognitive decline.
• Grn mice showed early RPE dysfunction, microglial activation, and photoreceptor loss.
• Loss of MTFP1 in Grn RPE led to mitochondrial hyperfusion, bioenergetic defects, and NF-kB-mediated C3aR activation, driving inflammation.

Conclusions:

• Progranulin deficiency disrupts RPE mitochondrial integrity via MTFP1, initiating a cascade of inflammation.
• Complement C3a-C3a receptor signaling exacerbates mitochondrial dysfunction and retinal inflammation.
• Targeting C3aR antagonism can restore mitochondrial function and reduce neuroinflammation in GRN-FTD.