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Abstract Details

Investigation of RAN Translation in SCA2
Movement Disorders
P05 - (-)
043
BACKGROUND: It has been shown that in some diseases caused by trinucleotide repeat expansions, translation can occur even in the absence of an ATG start codon. This repeat associated non-ATG translation (RAN translation) occurs across long, hairpin forming repeats and has been identified in spinocerebellar ataxia 8 and myotonic dystrophy type 1 (Ranum et al., 2011). Spinocerebellar ataxia type 2 (SCA2) is a disease caused by expansion of the CAG repeat length from 22 in healthy individuals to over 35 repeats in the disease state. The expanded CAG tract in ATXN2 forms hairpins and is therefore a good candidate for RAN translation.
DESIGN/METHODS: Control plasmids containing constructs of the ATXN2 gene with CAG repeat lengths of 1, 22, and 58 were made. Luciferase was cloned in-frame with the ATXN2-CAG repeat. Control plasmids and plasmids with the start codon mutated were transfected into HEK 293 cells. The efficacy of RAN translation in SCA2 was evaluated by comparing luciferase activity when no start codon was present to control plasmids containing start codons. Protein production was measured by luciferase assays and western blot analysis.
RESULTS: In both western blots and luciferase assays, removal of the effective start codon reduces gene expression nearly to background levels. This occurs regardless of repeat length, indicating that RAN translation is not effective in this model at producing protein in the absence of the start codon.
CONCLUSIONS: We conclude that the role of RAN translation in SCA2 is minimal.We cannot exclude, however, that cell-specific variants in the translation machinery may permit RAN translation in specific neuronal cell types.
Authors/Disclosures
Lance Petersen
PRESENTER 		No disclosure on file
No disclosure on file
Daniel R. Scoles, PhD, FAAN (University of Utah) The institution of Dr. Scoles has received research support from NIH.
Stefan M. Pulst, MD, FAAN (University of Utah) Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for venrock. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leverna. Dr. Pulst has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Leninthal LLC. The institution of Dr. Pulst has received research support from NINDS. Dr. Pulst has received intellectual property interests from a discovery or technology relating to health care.
Basil T. Darras, MD (Children'S Hosp Boston Harvard Med School) The institution of Dr. Darras has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Darras has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus. The institution of Dr. Darras has received research support from National Institutes of Health/National Institute of Neurological Disorders and Stroke,. The institution of Dr. Darras has received research support from Slaney Family Fund for SMA. The institution of Dr. Darras has received research support from Spinal Muscular Atrophy Foundation. The institution of Dr. Darras has received research support from CureSMA. The institution of Dr. Darras has received research support from Working on Walking Fund . The institution of Dr. Darras has received research support from CHERISH, CS2/CS12 . The institution of Dr. Darras has received research support from Biogen for CS11. The institution of Dr. Darras has received research support from AveXis. The institution of Dr. Darras has received research support from Sarepta Pharmaceuticals. The institution of Dr. Darras has received research support from PTC Therapeutics. The institution of Dr. Darras has received research support from Roche. The institution of Dr. Darras has received research support from Santhera. The institution of Dr. Darras has received research support from Scholar Rock. The institution of Dr. Darras has received research support from Fibrogen. The institution of Dr. Darras has received research support from Summit. Dr. Darras has received publishing royalties from a publication relating to health care. Dr. Darras has received publishing royalties from a publication relating to health care.