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Micropeptides translated from polymorphic upstream open reading frames: Lessons from doparesponsive dystonia

Journal of Neurology & Neurophysiology

ISSN - 2155-9562

Micropeptides translated from polymorphic upstream open reading frames: Lessons from doparesponsive dystonia

Joint Event on International Conference on Neuroimmunology, Neurological disorders and Neurogenetics & 28th World Summit on Neurology, Neuroscience and Neuropharmacology

September 26-27, 2018 | Montreal, Canada

Ioanna A Armata

Dr Georges L-Dumont University Hospital Center and University of Moncton, Canada

Scientific Tracks Abstracts: J Neurol Neurophysiol

Abstract :

Approximately 50% of human transcripts harbor potential upstream translation start sites (uATGs) that initiate short open reading frames (uORFs) in the five untranslated regions (5‚?? UTR) (Fig. 1A). Translation initiation at a uATG blocks a fraction of ribosomes from reaching the coding ATG (cATG) at the begging of the coding sequence (CDS). Thus, uATGmediated repression ensures that cATG-protein expression is maintained at optimal levels. Interestingly, some uORFs encode short bioactive proteins with roles different than the role of the CDS-encoded protein. Single nucleotide polymorphisms (SNPs) that ‚??introduce‚?Ě uATGs in genes that are normally devoid of uATGs, repress CDS translation below optimal levels. About 17 different diseases are linked with SNP-introduced uATGs, among which a single neurological syndrome identified by our work. In particular, carriers of a GCH1 +142C>T SNP manifest Dopa-Responsive Dystonia (DRD), a neurological movement disorder of childhood onset. The GCH1 gene encodes GTP cyclohydrolase 1, a critical enzyme for dopamine (DA) biosynthesis. The +142C>T SNP introduces a uATG/uORF that initiates translation upstream of the GCH1 CDS, diminishing GCH1 protein levels and disrupting DA biosynthesis (Fig. 1B). Furthermore, the introduced uORF translates a 73aa-peptide that accumulates in the nucleus of cultured cells, - in contrast to the cytoplasmic GCH1 -, triggering cellular death. Cases of DRD caused by coding GCH1 mutations are successfully treated with L-Dopa, which compensates for reduced DA levels. Assuming 73aa-triggered death of the dopaminergic-neurons within the brain of 142T patients, L-dopa might be insufficient for these patients, and dystonia could progressively manifest to Parkinson‚??s Disease. Noteworthy, while the translation of micro peptides from physiological uATGs/uORFs has been well demonstrated, only three studies have examined translation of microproteins from SNP-introduced uATGs/uORFs, and only the present study examined their impact on cellular homeostasis. Overall, our findings highlight the biological relevance of micro peptides translated from SNP introduced uATGs/uORFs.

Biography :

Armata is a molecular and cellular neuroscientist, who specializes in dystonia syndromes and myotonic dystrophy. Her training and expertise are in the fields of gene expression, functional non-coding mutations, assay development for drug high throughput screenings, and the CRISPR/Cas9 system. She has published over 10 peer-reviewed papers, four of which are related to the role of upstream open reading frames in neurological diseases. She obtained her PhD in Neuroscience at Mount Sinai School of Medicine (2008), followed by a postdoctoral fellowship (2008-2012) at Massachusetts General Hospital and Harvard Medical School, and a Research Faculty I appointment at Florida State University (2013-2016), until relocating to Canada for family reasons. At present, she is a Research Fellow holding a joint appointment at Dr. Georges-L.-Dumont University Hospital Centre and the University of Moncton, Canada, studying translational therapeutics for dystonia and myotonic dystrophy 1.

E-mail: [email protected]

 

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