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Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation
- Source :
- Human Molecular Genetics, 30(17), 1632-1648. Oxford University Press, Human Molecular Genetics
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 09646906
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics, 30(17), 1632-1648. Oxford University Press, Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....acbfcccb397f78d5322c5f7541aacd7a