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PNAS Papers on Fragile X-Associated Syndrome Modifier, Rabies Virus Expression Effects, More

Emory University researchers outline a role for the proteasome subunit-coding gene PSMB5 in modifying neurodegenerative features linked to a condition called fragile X-associated tremor/ataxia syndrome (FXTAS), a condition that is more common in individuals with FMR1 untranslated region expansion repeats. Using whole-genome sequencing, the team searched for genetic modifiers in male participants with this FMR1 UTR "premutation," uncovering candidate modifiers that were subsequently tested with functional experiments in the Drosophila fruit fly and in cell lines missing potential modifier genes. From 18 genes that seemed to tweak the neurotoxic effects of FXTAS-related expansion in Drosophila, the authors highlighted the apparent protective effects of dialing down PSMB5 expression, and say the results point to "a therapeutic strategy for FXTAS."

A team from the Salk Institute for Biological Studies, the University of California, San Diego, and the Allen Institute for Brain Science present findings from a single-nucleus RNA sequencing analysis of cortical neuron cells infected with the rabies virus. When they compared single-nucleus transcriptomes in rabies-infected and -uninfected cells in the mouse brain, the researchers tracked rabies-related transcriptional changes, along with cell type-specific gene expression features that are retained despite rabies infection. "[W]e find that rabies infection differentially affects distinct host genes," the authors note, "suggesting that some genes may be more vulnerable to transcriptional modulation than others, which may impede the classification of rabies-infected cells when using methods that rely on the detection of single or few genes."

Investigators at Nanjing Normal University and Yat-sen University Cancer Center link a long noncoding RNA (lncRNA) to brain metastasis in advanced breast cancer. The lncRNA, dubbed "brain metastasis oncogenic long noncoding RNA" (BMOR), was not only enriched in brain cells, but also appeared to drive breast cancer metastasis to the brain, the team notes. Based on findings from mouse model and other experiments, the authors suggest that BMOR dials down activity of the IRF3 interferon regulatory gene product, helping the cancer cells dodge immune activity. "[O]ur findings reveal a way in which cancer cells evade immune-mediated killing in the brain microenvironment for brain metastasis development," they write, "and establish therapeutic targets with potential targeted strategies against [breast-to-brain metastasis]."