Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation
| Autor: | Saif N Haify, Valerie Boumeester, Rob Willemsen, Lies-Anne Severijnen, Lucas Verwegen, Wang Yong Yang, Ronald A.M. Buijsen, Michael D. Cameron, Helen de Boer, Matthew D. Disney, Roos Monshouwer, Renate K. Hukema |
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| Přispěvatelé: | Clinical Genetics, Cell biology, Erasmus University Rotterdam |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
AcademicSubjects/SCI01140
Male RAD23B Ataxia Population Cell Communication Biology Fragile X Mental Retardation Protein Mice 03 medical and health sciences 0302 clinical medicine Tremor Genetics medicine Animals Humans education Molecular Biology Genetics (clinical) 030304 developmental biology Neurons 0303 health sciences education.field_of_study RNA Translation (biology) General Medicine FMR1 Small molecule DNA-Binding Proteins Disease Models Animal DNA Repair Enzymes Fragile X Syndrome Ran Cancer research General Article medicine.symptom Trinucleotide Repeat Expansion 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics, 30(17), 1632-1648. Oxford University Press Human Molecular Genetics |
| ISSN: | 0964-6906 |
| Popis: | Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected. FXTAS is caused by a CGG-repeat expansion (CGGexp) in the fragile X mental retardation 1 (FMR1) gene. CGGexp RNA is translated into the FMRpolyG protein by a mechanism called RAN translation. Although both gene and pathogenic trigger are known, no therapeutic interventions are available at this moment. Here, we present, for the first time, primary hippocampal neurons derived from the ubiquitous inducible mouse model which is used as a screening tool for targeted interventions. A promising candidate is the repeat binding, RAN translation blocking, small molecule 1a. Small molecule 1a shields the disease-causing CGGexp from being translated into the toxic FMRpolyG protein. Primary hippocampal neurons formed FMRpolyG-positive inclusions, and upon treatment with 1a, the numbers of FMRpolyG-positive inclusions are reduced. We also describe for the first time the formation of FMRpolyG-positive inclusions in the liver of this mouse model. Treatment with 1a reduced the insoluble FMRpolyG protein fraction in the liver but not the number of inclusions. Moreover, 1a treatment had a reducing effect on the number of Rad23b-positive inclusions and insoluble Rad23b protein levels. These data suggest that targeted small molecule therapy is effective in an FXTAS mouse model and has the potential to treat CGGexp-mediated diseases, including FXTAS. |
| Databáze: | OpenAIRE |
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