Huntingtin implicated in fragile X syndrome

Researchers at the University of Wisconsin have discovered a link between fragile X syndrome (FXS) and Huntingtin (Htt) protein, better known for its role in Huntington's disease (HD). FXS is the most common cause of intellectual disability, and is critical for the regulation of neuronal development, but at a molecular level, the functions of Fragile X Mental Retardation Protein (FMRP), which is nonfunctional in FXS, remain unclear. The researchers showed that "FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knockdown and Fmr1-knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of fragile X syndrome." They published their findings in the Feb. 11, 2019, online issue of Nature Neuroscience.

NTHL1 mutations lead to tumor predisposition syndrome

Researchers at Radboud University and Princess Maxima Cancer Center have demonstrated that germline mutations in both copies of NTHL1 predisposed to multiple types of tumors. Mutations in NTHL1 had previously been linked to colorectal cancer, but in an analysis of 29 individuals with mutations in both copies of NTHL1, the team showed that such individuals were prone to developing tumors in multiple different organs. Twenty six of the individuals developed at least one tumor, and 16 individuals developed multiple tumors in a total of more than a dozen anatomical sites. The incidence of breast tumors was particularly striking, as more than half of female carriers developed breast cancer. "These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome," the authors wrote. Their work appeared in the Feb. 11, 2019, issue of Cancer Cell.

Drop the MIC? At least add to it

Scientists at Uppsala University have shown that in an analysis of roughly 40 clinical isolates of Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii that they tested for susceptibility of nearly 30 different antibiotics, roughly a quarter of bacteria/antibiotic combinations that tested as susceptible using minimal inhibitory concentration (MIC) testing had resistant subpopulations, a phenomenon known as heteroresistance. The authors showed that "a majority of heteroresistance cases were unstable, with an increased resistance of the subpopulations resulting from spontaneous tandem amplifications, typically including known resistance genes." Using mathematical modeling, they also demonstrated that "heteroresistance in the parameter range estimated in this study can result in the failure of antibiotic treatment of infections with bacteria that are classified as antibiotic susceptible." They concluded that their work, which appeared in the Feb. 11, 2019, online issue of Nature Microbiology, "highlights the limitations of MIC as the sole criterion for susceptibility determinations."

Glial alpha-synuclein causes neuronal toxicity

Researchers from Institute of Biomedicine of the University of Barcelona have demonstrated that alpha-synuclein from glial cells contributed to neuronal toxicity in cell culture cx models of Parkinson's disease (PD). Toxic aggregations of alpha-synuclein known as Lewy bodies are a pathological hallmark of PD and a group of neurodegenerative disorders, collectively, the synucleinopathies. There have been some hints, but no direct demonstration, that alpha-synuclein produced by other cell types could contribute to neuronal toxicity. In their work, the team co-cultured astrocytes derived from induced pluripotent stem cells (iPSCs) from patients with a mutation in the leucine-rich repeat kinase (LRRK), with iPSC-derived neurons without this mutation, which is a major PD risk mutation. They showed that the neurons, which lacked the mutation, nevertheless accumulated toxic alpha-synuclein. "Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells," the authors wrote. Their work appeared in the Feb. 12, 2019, print issue of Stem Cell Reports after earlier publication online.

Decoy platelets for thrombosis, metastasis

A team from Harvard University's Wyss Institute for Biologically Inspired Engineering and The George Washington University has gained new insights into the relationship between thrombosis and metastasis, and demonstrated that "decoy" platelets could prevent both harmful blood clots and metastases in animal models. Current antiplatelet drugs are clinically effective, but they also increase the risk of bleeding, and reversing their effects requires making new platelets and this takes a week to 10 days, which can make them life-threatening in emergencies. The team showed that platelet decoys that retained the binding abilities of platelets, but not their ability to activate other platelets, could interfere with both arterial injury-induced thromboembolism and platelet-mediated human breast cancer cell aggregation. The effects of the decoys could be "immediately reversed" by administering normal platelets, leading the authors to suggest that "platelet decoys might represent an effective strategy for obtaining antithrombotic and antimetastatic effects." They published their results in the Feb. 13, 2019, issue of Science Translational Medicine.

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