Activity-dependent neuroprotective protein (ADNP) is essential for brain formation, and mutations in the ADNP-encoding gene have been linked to an autism-like syndrome in children that is characterized by developmental delay along with intellectual and social disabilities. An 8-amino acid motif derived from ADNP (referred to as NAP) has been shown to be neuroprotective, via enhancing dendritic spine formation, in mice lacking ADNP. In this episode, Illana Gozes and colleagues characterize Adnp+/- mice as a model of ANDP syndrome. Adnp+/- animals had reduced dendritic spine density, developmental delays, impaired vocalizations, and motor dysfunction along with memory and social impairment. Administration of NAP partially reversed behavior and developmental defects and increased dendritic spine density. The results of this study support further exploration of NAP administration for treatment of ADNP syndrome.
Graft-versus-host-disease (GVHD) is a life-threatening complication of allogeneic BM transplantation that affects skin, liver, and the gastrointestinal (GI) tract. GI involvement is associated with the most severe form of disease and outcomes for these patients are poor. Treatments for GVHD are limited; therefore, a better understanding of markers of GI involvement have potential to improve treatment. In this episode, James Ferrara and colleagues identify the Paneth cell protein regenerating islet-derived 3α (REG3α) as a biomarker that is upregulated in sera of patients with GI GVHD. Moreover, using murine models, the authors determined that REG3α, which has well-known antimicrobial function, promotes intestinal stem cell survival; thereby, protecting the intestinal barrier. Together, these results indicate that strategies to increase REG3α should be explored for limiting GI GVHD.
Prostate cancer is an androgen-dependent disease; therefore, current approaches for treatment aim to disrupt androgen signaling. Unfortunately, this approach is rarely curative due to the selection of resistant clones and adaptation of stromal and endothelial cells to support tumor growth. In this episode, Neil Bhowmick and colleagues evaluated epigenetic alterations in prostate cancer-associated fibroblasts (CAFs) and determined that the Ras inhibitor RASAL3 is silenced in these cells, thereby driving macropinocytosis-mediated glutamine synthesis due to increased oncogenic Ras activity. The increase in stromal glutamine associated with neuroendocrine differentiation, and in prostate cancer patients, blood glutamine levels were elevated in patients that were resistant to androgen deprivation compared to those that were responsive. Together, these results suggest that strategies to prevent glutamine uptake be considered in conjunction with androgen deprivation.
Upwards of 10% of all bone fractures fail to heal properly, with dysfunctional repair even more common in individuals with metabolic defects. Vitamin D has been implicated in fracture healing, which involves formation of a soft callus at the fracture site that is later mineralized and ossified. In this episode, René St-Arnaud and colleagues determined that that ossification is impaired in Cyp24a1-deficient mice, which are unable to synthesize the vitamin D metabolite 24R,25-dihydroxyvitamin D3, following traumatic bone injury. FAM57B2 was upregulated in the fracture callus of Cyp24a1-deficient mice and an interaction between FAM57B2 and 24R,25-dihydroxyvitamin D3 in chondrocytes produced lactosylceramide, which supports callus mineralization. Importantly, lactosylceramide supplementation improved mineralization in both Cyp24a1- and Fam57b2-deficient calluses, suggesting that this 24R,25-dihydroxyvitamin D3–dependent pathway has potential to be targeted to optimize bone repair after fracture.
Podocyte dysfunction is a hallmark of kidney injury and occurs in both autoimmune and nonautoimmune renal diseases. Calcium signaling underlies podocyte injury; however, the factors that promote calcium signaling in podocytes in response to injury are not fully understood. In this episode, George Tsokos and colleagues demonstrate that Ca2+/calmodulin–dependent kinase 4 (CaMK4) is increased in podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and in mouse models of lupus and kidney injury. Moreover, administration of a CaMK4 inhibitor prevented nephritis in lupus-prone mice and ameliorated podocyte damage in mice with kidney injury. Togeither, this study identifies CaMK4 activation as a driver of podocyte dysfunction and suggests CaMK4 inhibition be further explored for treating podocytopathies.