Here researchers report on a novel form of pathological protein aggregation in the aging brain and evidence for it to contribute to mitochondrial dysfunction in Alzheimer's disease. This phosphorylated GRK2 aggregation is argued to be a downstream effect of the other well-known forms of protein aggregation in the condition, those involving amyloid-β and tau, though that remains to be definitively proven. Certainly, given the inability of clearance of amyloid-β to produce sizable effects on the progression Alzheimer's disease, one might imagine other mechanisms are more involved in triggering GRK2 aggregation. Regardless, reducing GRK2 aggregation improves function in mouse models of Alzheimer's disease, suggesting some value in targeting this process.
The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L.
Aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 (translocase of outer mitochondrial membrane 6), promotes mitochondrial dysfunction, and enhances beta-amyloid. Transgenic expression of inactive GRK2-K220R or a GRK-inhibitory peptide proves that neuropathological features are caused by GRK2 inactivation. Restoration of TOMM6 by neuron-specific TOMM6 expression reduces beta-amyloid plaques but enhances soluble beta-amyloid and increases mortality. In contrast, reconstitution of monomeric GRK2 and proteasomal phospho-S670-GRK2 degradation by small molecules counteracts neuropathological AD features, prevents neuronal loss, and improves survival. Thus, targeting of pathological GRK2 aggregation slows aging-induced neurodegeneration.
Link: https://doi.org/10.1016/j.xcrm.2026.102707
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