Proceedings of the National Academy of Sciences · 2020 · 141 citations · 35 references
Life SciencesMolecular BiologyNeuroscienceGene ExpressionGene TherapyNeurodegenerationAmyotrophic Lateral SclerosisMolecular Basis Of NeurodegenerationNeurodegenerative Disease PharmacotherapyNeurodegenerative DiseasesNeurodegenerative DisordersProtein SynthesisC9orf72 Repeat ExpansionGene-targeted TherapyNeurodegenerative Disease Gene TherapyNeurodegenerative Pathway MechanismsProtein ProductionRepeat Expansion DisordersRepeat Expansion MutationsRepeat Expansion Targeting
Significance Repeat-associated non-AUG (RAN) proteins accumulate in patient brains and contribute to a growing number of neurodegenerative diseases. There is an urgent need to understand why expression of these proteins does not require canonical or near-cognate AUG start codons and to develop ways to block RAN protein production. We show several types of repeat-expansion RNAs activate the double-stranded RNA-dependent protein kinase (PKR) pathway and that blocking PKR reduces RAN protein levels in cells. PKR is activated in C9orf72 ALS/FTD human and mouse brains and PKR inhibition using AAV-PKR-K296R or the FDA-approved drug metformin decreases RAN protein levels and improves disease in ALS/FTD mice. Targeting PKR using gene therapy or metformin are promising therapeutic approaches for C9orf72 ALS/FTD and other expansion diseases.
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Kohji Mori, Shih‐Ming Weng, Thomas Arzberger et al. · Science · 2013 · 1.3K citations
Life Sciences, Genetics, Neurology +17