Although numerous studies have demonstrated that poor sleep increases the development of AD, direct evidence elucidating the benefits of good sleep on the AD pathogenesis is lacking. Familial Natural ...Short Sleepers (FNSS) are genetically wired to have lifelong reduction in nightly sleep duration without evident consequence on cognitive demise, implying that they may have better sleep quality. Here we investigated two FNSS mutations, DEC2-P384R and Npsr1-Y206H, on the development of tau and amyloid pathology in AD-like mouse models. We found that the development of tau pathology is attenuated in the hippocampus of tau mice carrying FNSS mutations. We also found that DEC2-P384R;5XFAD and female Npsr1-Y206H;5XFAD mice exhibit significantly less amyloid plaques than control mice at 6 months of age. Together, these results reveal that these two FNSS alleles are strong genetic modifiers of AD pathology and may confer resilience to the progression of tau pathology and amyloid plaque formation in neurodegeneration.
Display omitted
•Two FNSS mutations are strong genetic modifiers of AD-like pathology in mice•Mutant DEC2 and Npsr1 reduced tau pathology in PS19 mouse model of tauopathy•Mutant DEC2 and Npsr1 slowed down amyloid plaques in 5XFAD APP transgenic mouse model•Efficient sleep may be an exciting therapeutic target for ameliorating AD development
Behavioral neuroscience; Biological sciences; Molecular neuroscience
Microsatellite instability high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a ...frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
Display omitted
•RPL22 p.K15fs mutations are highly prevalent in MSI-H cell lines and tumors•RPL22 mediates alternative splicing and expression of its paralog RPL22L1•RPL22 loss increases MDM4 exon 6 inclusion, augmenting protein expression of MDM4•RPL22 modulates the MDM4-p53 pathway thereby revealing it as a tumor suppressor in cancer
Weinstein et al. show loss of ribosomal gene RPL22 promotes alternative splicing of its paralog RPL22L1 and inclusion of MDM4 exon 6, leading to increased MDM4 expression. These findings reveal a common splicing circuit in MSI-H tumors, adding RPL22 to the regulators of the MDM4-p53 axis and oncogenic RPL22L1 induction.
