Abstract
Down’s syndrome (DS; also known as trisomy 21; T21) is caused by a triplication of all or part of human chromosome 21 (chr21). DS is the most common genetic cause of intellectual disability attributable to a naturally-occurring imbalance in gene dosage. DS incurs huge medical, healthcare, and socioeconomic costs, and there are as yet no effective treatments for this incapacitating human neurogenetic disorder. There is a remarkably wide variability in the ‘phenotypic spectrum’ associated with DS; the progression of symptoms and the age of DS onset fluctuate, and there is further variability in the biophysical nature of the chr21 duplication. Besides the cognitive disruptions and dementia in DS patients other serious health problems such as atherosclerosis, altered lipogenesis, Alzheimer’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), autoimmune disease, various cancers including lymphoma, leukemia, glioma and glioblastoma, status epilepticus, congenital heart disease, hypotonia, manic depression, prostate cancer, Usher syndrome, motor disorders, Hirschsprung disease, and various physical anomalies such as early aging occur at elevated frequencies, and all are part of the DS ‘phenotypic spectrum.’ This communication will review the genetic link between these fore-mentioned diseases and a small group of just five stress-associated microRNAs (miRNAs)—that include let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802—encoded and clustered on the long arm of human chr21 and spanning the chr21q21.1-chr21q21.3 region.
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Acknowledgements
This Research Work was presented in part at the Alzheimer Association International Congress 2016 (AAIC 2016) Annual conference 21–27 July 2016 in Toronto Canada and at the 13th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2017) 29 March–2 April in Vienna Austria. Thanks are also extended to the many neuropathologists, physicians and researchers of the US, Canada, and Europe for helpful discussions and who have provided high quality, short post-mortem interval (PMI) human CNS, extracted tissue fractions and/or bioinformatics data for scientific analysis and study and to Drs. Christoff Eicken, Chris Hebel, Kyle Navel, Aileen Pogue and Darlene Guillot for expert technical assistance, organization and medical artwork. Research on the pro-inflammatory and pathogenic signaling in the Lukiw laboratory involving the innate-immune response, neuroinflammation, and amyloidogenesis in AD, PD, DS, retinal and prion disease, and in other neurological diseases was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN) and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834.
Author Contributions
PNA, MEP and WJL discussed the genomic data and scientific implications of these ideas; WJL researched and wrote this paper; the authors are sincerely grateful to colleagues and collaborators for helpful discussions and for sharing unpublished data.
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Alexandrov, P.N., Percy, M.E. & Lukiw, W.J. Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down’s Syndrome and Trisomy-21 Linked Disease. Cell Mol Neurobiol 38, 769–774 (2018). https://doi.org/10.1007/s10571-017-0514-0
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DOI: https://doi.org/10.1007/s10571-017-0514-0