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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” ((https://www.biorxiv.org/content/biorxiv/early/2019/01/24/529768.full.pdf). 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. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the ‘polyglutamine disorders.’” In their full article, the authors say that their results “indicate that the driver of the rate of HD pathogenesis leading to diagnosis is not the length of the polyglutamine tract in huntingtin, but rather the length of the uninterrupted CAG repeat segment in the HTT gene. These findings cement the role of DNA maintenance mechanisms in modifying HD pathogenesis, most likely through an influence on somatic expansion of the HTT uninterrupted CAG repeat, and they disclose new loci that may influence HD pathogenesis through other mechanisms.” Note that the preprint described here has not been peer-reviewed.

RELATED THEORY OF POSSIBLE HD DISEASE MECHANISM

Consistent with this new view of HD, Jonathan Monkemeyer, EE, has created a video ("The Blue Solution") describing a compelling theory on the possible molecular origins of HD, namely that during transcription of the excessive number of CAG repeats in those with HD, the mRNA being created can, because of its unusual length and repetitive sequence, loop back on itself, forming regions of double-stranded (ds) RNA. Such ds RNA is a stranger in the cell, and is associated, by the cell, with the presence of a virus, and the cell proceeds to trigger a powerful immune response to a possible dangerous invader. According to the theory presented in Jonathan’s video, this misguided immune assault is at the root of HD. Here, and below, are links to both the short introductory section of the video (https://www.youtube.com/watch?v=JnkhVBWkX7k&feature=youtu.be&t=9m34s) and also to the full video (19 minutes) (https://www.youtube.com/watch?v=JnkhVBWkX7k).

In the video, Jonathan notes that, if this proposed mechanism is really the problem, the simple and once readily available compound methylene blue might be effective because it could prevent the mRNA from becoming double-stranded.

Jonathan, a former world-class electrical engineer who worked for the GE Space Program, lost his wife to HD, and, since that tragic loss, has devoted almost all of his time and efforts, to trying to understand HD and to investigating possible approaches to treatment and even a cure. He brings his different engineering perspective to the baffling puzzle of HD, and provides possibly unique insights on the possible molecular mechanism of this terrible disease. BioQuick News would strongly encourage anyone interested in HD to view Jonathan’s entire video (https://www.youtube.com/watch?v=JnkhVBWkX7k).

In speaking with BioQuick News, Jonathan said that he is currently highly focused on efforts to repurpose existing drug to treat the common critical pathways of neurodegeneration and autoimmune disease. Also, together with Patrick Brundin, MD, PhD, Director of the Center for Neurodegenerative Science at the Van Andel Research Institute (https://www.vai.org/) in Grand Rapids, Michigan, he is seeking funding to gain clinical evidence of which existing drugs can stop Huntington’s disease (HD)/Juvenile Huntington’s disease (JHD).

Jonathan said that their patient-centric initiative is to save the lives of those suffering now by quickly repurposing safe existing drugs, until a more effective solution becomes available.

Dr. Brundin’s lab (https://patrikbrundinlab.vai.org/) currently focuses on pathogenetic mechanisms and pharmacological treatment in cell and animal models of Parkinson’s disease. The group’s mission is to understand neurodegenerative diseases and develop new therapies that are of benefit to patients and their caregivers.

FAMILY TOLL TAKEN BY HUNTINGTON’S DISEASE

Here are two links that Jonathan provided to stories about the struggles of families coping with Huntington’s disease. These stories drive powerfully home how urgent it is to understand and treat, and hopefully cure, Huntington’s disease (https://blogs.plos.org/dnascience/2015/05/28/can-we-cure-huntingtons-dis...) and (http://curehd.blogspot.com/2013/02/no-marine-deserted-on-battlefield-two...).

Jonathan said those who wish to follow the struggle may follow his posts on Facebook (Jonathan W Monkemeyer).

[Preprint from Cold Spring Harbor Laboratory] [Monkemeyer video (Introduction)] [Monkemeyer video (Complete)] [Huntington disease story 1] [Huntington disease story 2]