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Archive - Mar 14, 2019

Huntington Disease Rate of Progression Determined by Length of Uninterrrupted CAG Repeats in DNA, Not Length of Polyglutamine Segment of Mutant Huntingtin Protein; Results Point to Importance of DNA Maintenance Mechanisms

HIn a preprint posted on January 24, 2019 by Cold Spring Harbor Laboratory’s bioRxiv, the Genetic Modifiers of Huntington’s Disease Consortium (GeM-HD), including such prominent HD experts as James Gusella, PhD, and Marcy MacDonald, PhD, both of the Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital; and Jane Paulsen, PhD, Departments of Psychiatry and Neurology, University of Iowa, make the provocative suggestion that some property of the uninterrupted CAG repeat segment in exon 1 of the huntingtin-coding gene (HTT), distinct from the resulting too-lengthy polyglutamine segment of the huntingtin protein, determines the rate at which HD develops. The article is titled “Huntington's Disease Onset Is Determined by Length of Uninterrupted CAG, Not Encoded Polyglutamine, and Is Modified by DNA Maintenance Mechanisms” (( According to the article abstract, “The timing of onset shows no significant association with HTT cis-eQTLs, but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms.

Heart Uses Exosomes to Send SOS Signal to Bone Marrow (BM) Cells After Heart Attack; In BM, Exosomes Release Heart-Specific MicroRNAs That Down-Regulate CXCR4 & Stimulate BM Progenitor Cells to Enter Blood Stream & Travel to Heart to Attempt Repairs

Human cells release exosomes. These tiny, membrane-bound vesicles can carry cargo for cell-to-cell communication, with the ability to ferry diverse loads of proteins, lipids, and/or nucleic acids. Researchers at the University of Alabama at Birmingham (UAB) and in China now report that exosomes are key to the SOS signal that the heart muscle sends out after a heart attack. After the heart attack, the exosomes in the bloodstream carry greatly increased amounts of heart-specific microRNAs — an observation seen in both mice and humans. These exosomes preferentially carry the microRNAs to progenitor cells in the bone marrow. Inside those progenitor cells, the microRNAs turn off a specific gene that allows the progenitor cells to leave the bone marrow and enter the bloodstream. The cells then travel to the heart to attempt repairs. The investigators say discovery of this novel pathway — a signal from the damaged heart to a systemic response by the reparative bone marrow cells — can now be leveraged to improve cell-based cardiovascular repair after heart attacks. The study — led by Gangjian Qin, MD, Professor in the UAB Department of Biomedical Engineering and Director of the Molecular Cardiology Program, and Min Cheng, MD, PhD, Huazhong University of Science and Technology, Wuhan, China — was published online on February 27, 2019 in Nature Communications. The open-access article is titled “Circulating Myocardial MicroRNAs from Infarcted Hearts Are Carried in Exosomes and Mobilize Bone Marrow Progenitor Cells.” For 15 years, it had been known that progenitor cells are released from the bone marrow after a heart attack. These cells move to the damaged heart muscle to attempt repairs. However, many efforts to improve that repair have yielded only modest efficacies, at best.