The Hippo pathway shows up in many areas of research into aging, regeneration, cancer, and cellular senescence. This tends to be the case for protein machinery that is involved in cell growth and cell stress responses, including programmed cell death. See the research surrounding nutrient signaling and its relationship with cell growth, centering around mTOR and its surrounding biochemistry, for example. Hippo signaling is fairly complex, but also quite well explored. Nonetheless while individual protein interactions in the pathway are well mapped, how it operates in detail to produce different outcomes in different contexts is less well understood. Its activities regulate both cell proliferation and cell death via apoptosis, both relevant to regeneration, cancer, and aging, among other topics.
In different contexts, researchers have assessed the merits of both inhibition of Hippo signaling to enhance regeneration, suppress cellular senescence and cell death, or encourage the death of cancerous cells. Here, researchers provide evidence for Hippo pathway inhibition to be a path to making the aging brain more resilient to metabolic imbalances that lead to excessive programmed cell death. Ferroptosis is one such cell death pathway, a consequence of dysregulated iron metabolism, and of late shown to be a relevant pathological mechanism in aged tissues. Inducing a lesser degree of ongoing ferroptosis may be protective in the aging brain.
The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity.
Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis.
These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.
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