Mutations in presenilins (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer’s disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid precursor protein (APP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the “functional” mutations for ER Ca2+ leak were clustered in the exon 8–9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis (CWP/SP) clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the “functional” and “non-functional” PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout (DKO) mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

Hox genes are crucial determinants of cell fates and of body morphology of animals; mutations affecting these genes result in abnormal patterns of programmed cell death. How Hox genes regulate programmed cell death is an important and poorly understood aspect of normal development. In the nematode C. elegans, the Hox gene mab-5 is required for the programmed cell deaths of two lineally related cells generated in the P11 and P12 lineages. We show here that in the P11 lineage, a complex between MAB-5 and the Pbx homolog CEH-20 directly regulates transcription of the BH3 domain gene egl-1 to initiate programmed cell death; in the P12 lineage, mab-5 and ceh-20 apparently act indirectly to initiate programmed cell death. Direct regulation of programmed cell death may be an evolutionarily ancient and conserved function of Hox genes.

Objective The efficacy of tofacitinib in early diagnosis of MDA5-ILD has been described. But whether tofacitinib exposure is associated with a reduced one-year mortality remains undetermined. Methods Patients diagnosed as MDA5-ILD receiving tofacitinib or tacrolimus treatment were included. Cox proportional hazards model adjusted for age, sex, smoking history, anti-MDA5 antibody titers, concurrent use of other steroids sparing agents was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality in the two treatment groups. Results During the study period, twenty-six patients were treated with tofacitinib and thirty-five with tacrolimus. The 6-month and 1-year mortality in tofacitinib group were significantly lower than those in tacrolimus group (38.5% vs. 62.9%, p=0.028; 44.0% vs. 65.7%, p=0.031, respectively). There were thirteen patients diagnosed as rapidly progressive-ILD (RPILD) in tofacitinib group and twenty-two in tacrolimus group. The majority of death occurred in patients with RPILD. The 6-month and 1-year mortality of patients with RPILD in tofacitinib group were also lower than those in tacrolimus group (76.9% and 95.5%, p=0.021; 84.6% and 100.0%, p=0.017). The adjusted model showed tofacitinib exposure was associated with a lower risk for 1-year mortality (HR0.438, 95% CI 0.200-0.960, p=0.039). While the incidence of adverse events and medication discontinuation rates between the two groups were similar (73.1% and 74.3%, p=1.000; 23.1% and 14.3%, p=0.504). Conclusion Our observational study showed tofacitinib use might have a potential impact on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of tofacitinib.

Remyelination plays a key role in functional recovery of axons after spinal cord injury. Glial cells are the most abundant cells in the central nervous system. When spinal cord injury occurs, many glial cells at the lesion site are immediately activated, and different cells differentially affect inflammatory reactions after injury. In this review, we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process. Activated astrocytes influence proliferation, differentiation, and maturation of oligodendrocyte precursor cells, while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury. Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

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