In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including ␣-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX ⌬E2 mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX ⌬E2 mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX ⌬E2 mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX ⌬E2 mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX ⌬E2 mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX ⌬E2 mice may contribute to mental retardation syndromes seen in human patients.

AbstractNaked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these “contradicting” features by a phenomenon termed “senescent cell death (SCD)”—Senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system. In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR-fibroblasts induce SCD through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage and accelerated H2O2-releasing metabolic pathways. During senescence, NMR cells showed resistance to metabolic remodelling unlike mice. Our findings provide mechanistic insights into how extraordinary aging resistance is accomplished in NMR. This will contribute to the development of senolytic drugs to regulate age-related diseases.

Naked mole‐rats (NMRs) have exceptional longevity and are resistant to age‐related physiological decline and diseases. Given the role of cellular senescence in aging, we postulated that NMRs possess unidentified species‐specific mechanisms to prevent senescent cell accumulation. Here, we show that upon induction of cellular senescence, NMR fibroblasts underwent delayed and progressive cell death that required activation of the INK4a‐retinoblastoma protein (RB) pathway (termed “INK4a‐RB cell death”), a phenomenon not observed in mouse fibroblasts. Naked mole‐rat fibroblasts uniquely accumulated serotonin and were inherently vulnerable to hydrogen peroxide (H2O2). After activation of the INK4a‐RB pathway, NMR fibroblasts increased monoamine oxidase levels, leading to serotonin oxidization and H2O2 production, which resulted in increased intracellular oxidative damage and cell death activation. In the NMR lung, induction of cellular senescence caused delayed, progressive cell death mediated by monoamine oxidase activation, thereby preventing senescent cell accumulation, consistent with in vitro results. The present findings indicate that INK4a‐RB cell death likely functions as a natural senolytic mechanism in NMRs, providing an evolutionary rationale for senescent cell removal as a strategy to resist aging.