Developmental origins of pediatric brain tumors
Many pediatric brain tumors occur in specific time windows of childhood. For that reason, such tumors are thought to have their origins in faulty prenatal development. Scientists at McGill University and the University of Toronto have gained new insights into what those faults are in several pediatric tumors. The authors conducted a thorough analysis of both the cortex and specific brainstem structures during development in mice, as well as in fetal brains of the early second trimester. Comparing their developmental transcriptomic data with tumor transcriptomes, they were able to identify the developmental origins of WNT medulloblastomas and atypical teratoid/rhabdoid tumors. “Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages,” the authors wrote. “Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.” Their work appeared in the Nov. 25, 2019, online issue of Nature Genetics.
New cholesterol target works independently of LDL receptor
Investigators at Beth Israel Deaconess Medical Center have identified the orphan G protein-coupled receptor GPR-146 as a possible target for cholesterol-lowering therapeutics. The team was looking for potential therapeutics development options for individuals with the genetic disorder homozygous familial hypercholesteremia. Individuals with the disorder are at very high risk of heart disease due to mutations in both copies of their low-density lipoprotein (LDL) cholesterol receptor, which leads to very high levels of circulating “bad” LDL cholesterol. Both statins and PCSK9 inhibitors work via effects on the LDL receptor, which is not helpful when that receptor is not functional. The authors focused on GPR-146 because of previous reports that it lowered plasma cholesterol levels, and showed that its actions did not require functional LDL cholesterol receptors. The team showed that atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR deficient mice upon GPR-146 depletion, and concluded that GPR-146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.” They published their study in the Nov. 27, 2019, issue of Cell.
Prion protein with gain of function found
Prion proteins can aggregate and act as infectious particles. When prions aggregate, they usually do so in amyloid fibrils, which leads to loss of function. Now, researchers at Stanford University have demonstrated that the RNA-binding protein Vts1/SMAUG could also aggregate into infectious prions. However, aggregation made SMAUG more effective at its function, which is to down-regulate its target proteins. The team also showed that aggregated SMAUG was capable of “[rewiring] posttranscriptional gene expression landscapes to favor robust mitotic growth.” The authors concluded that “self-assembly of RNA-binding proteins can drive a form of epigenetics beyond the chromosome, instilling adaptive gene expression programs that are heritable over long biological timescales.” Their work appeared in the Nov. 19, 2019, online issue of Molecular Cell.
Impaired ATM function linked to worse rheumatoid arthritis
A group from Yale University has shown that mutations in the ataxia-telangiectasia mutated (ATM) protein led to bone erosion in mouse models of rheumatoid arthritis (RA). ATM is best known for its role in DNA repair, but the researchers showed that in RA, mutations that impaired its function led in B cells to increased production of the proinflammatory RANK ligand and favored bone breakdown. The gene also affected B-cell receptor recombination, leading to an altered repertoire of antibody-producing B cells. “It remains to be determined whether the altered B cell repertoire induced by decreased ATM function in RA may contribute to disease pathogenesis or is solely a by-product of improper ATM expression in developing B cells,” the authors wrote. “Identifying patients with RA and decreased ATM function… which [correlates] with high prevalence of erosive disease, may have implications for improving our understanding, diagnosis, and treatment of RA with the growing arsenal of biologic monoclonal antibody and small-molecule inhibitor therapies.” They published their study in the Nov. 20, 2019, issue of Science Translational Medicine.
ALS exomes identify new culprit
Researchers at the Broad Institute of Harvard and MIT have used exome sequencing to identify the gene DNAJC7 as a previously new amyotrophic lateral sclerosis (ALS) risk gene. The team compared exome sequences of more than 3,000 ALS patients and more than 7,000 controls to identify risk genes that have not been found in pedigree studies. The study was able to identify known ALS risk genes, including SOD1 and FUS, and identified DNAJC7 as a new risk gene. DNAJC7 codes for a member of the heat-shock protein family, which collectively function as chaperones that help ensure proper folding of other proteins. The team reported its findings in the Nov. 25, 2019, online issue of Nature Neuroscience.