Two separate teams of researchers have shown that inhibiting polo-like kinase 4 (PLK4) specifically killed cells with high levels of the ubiquitin ligase TRIM37. High TRIM37 levels occur in subsets of breast cancers and neuroblastomas, due to chromosomal abnormalities on chromosome 27. Among the targets of TRIM37 are pericentriolar material. To divide properly, cells need either structures called centrosomes or pericentriolar material. PLK4 inhibition damages centrosomes, and is synthetic lethal to cells with high TRIM37 levels, which already lack pericentriolar material. The findings were published in back to back papers by a team at the University of California at San Diego and a collaboration of Oxford University and Johns Hopkins University, respectively. They appeared in the Sept. 9, 2020, issue of Nature.

Angiopoietin trouble can lead to lymphedema

Scientists at the University of Helsinki and the University of Louvain have identified angiopoietin (ANGPT) mutations as a contributor to primary lymphedema. Edema, the accumulation of fluid in the limbs because of insufficient drainage of the lymph system, most often occurs as a result of damage to the lymph system, which can be due to diverse causes including medical treatments and parasite infections. Primary lymphedema is at least in part genetic, but although there are nearly 30 genes that have been identified as causal factors, those genes collectively can explain fewer than 30% of cases. In their work, the authors screened more than 500 study participants with primary lymphedema, and identified gene deletions or mutations of ANGPT2 in five cases. ANGPT2 usually stimulates vessel growth through its receptors, TIE1 and TIE2. The authors concluded that their results “demonstrate that primary lymphedema can be associated with ANGPT2 mutations and provide insights into TIE1 and TIE2 activation mechanisms.” Their work appeared in the Sept. 9, 2020, issue of Science Translational Medicine.

Toxicity, infectivity separate issues for prion protein

Researchers at University College London have uncoupled prion protein toxicity from its infectivity, a finding, they wrote, that “has fundamental implications for understanding of prion diseases and how to treat them and may have wide relevance in other neurodegenerative diseases which involve propagation and spread of proteopathic seeds.” Prions are infectious proteins that misfold, aggregate, and propagate from cell to cell. Prion infections underlie a variety of neurodegenerative diseases in different species, including Creutzfeldt-Jacob disease in humans. The assumption has been that prion proteins are directly toxic, but when the authors directly tested that assumption using highly purified prion proteins, they found that while “brain homogenates from symptomatic prion-infected mice [were] highly toxic to cultured neurons, exceptionally pure intact high-titer infectious prions [were] not directly neurotoxic.” Treatment with detergent sarkosyl could “destroy toxicity without diminishing infectivity.” The authors concluded that “the lack of detectable direct toxicity of highly purified prion preparations or sarkosyl-treated infected brain homogenate is consistent with models of prion neurotoxicity being mediated by [prion protein species] which are distinct from fibrillar infectious prion assemblies and which may be generated by a distinct mechanistic process, although further studies are required to confirm the identity of neurotoxic species.” Their work appeared in the Sept. 8, 2020, online issue of the Proceedings of the National Academy of Sciences.

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