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Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation.

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 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 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 number 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 a FXTAS mouse model and has potential to treat CGGexp-mediated diseases, including FXTAS.

SUBMITTER: Haify SN

PROVIDER: S-EPMC8369842 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Fragile X premutation (Amplification of CGG number 55-200) is associated with increased risk for fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and fragile X-associated tremor/ataxia syndrome (FXTAS) predominantly in males. Recently, it has been shown that CGG repeats trigger repeat associated non-AUG initiated translation (RAN) of a cryptic polyglycine-containing protein, FMRpolyG. This protein accumulates in ubiquitin-positive inclusions in neuronal brain cells of FXTAS patients and may lead to protein-mediated neurodegeneration. FMRpolyG inclusions were also found in ovary stromal cells of a FXPOI patient. The role of FMRpolyG expression has not been thoroughly examined in folliculogenesis related cells. The main goal of this study is to evaluate whether FMRpolyG accumulates in mural granulosa cells of FMR1 premutation carriers. Following FMRpolyG detection, we aim to examine premutation transfected COV434 as a suitable model used to identify RAN translation functions in FXPOI pathogenesis. RESULTS:FMRpolyG and ubiquitin immunostained mural granulosa cells from six FMR1 premutation carriers demonstrated FMRpolyG aggregates. However, co-localization of FMRpolyG and ubiquitin appeared to vary within the FMR1 premutation carriers' group as three exhibited partial ubiquitin and FMRpolyG double staining and three premutation carriers demonstrated FMRpolyG single staining. None of the granulosa cells from the five control women expressed FMRpolyG. Additionally, human ovarian granulosa tumor, COV434, were transfected with two plasmids; both expressing 99CGG repeats but only one enables FMRpolyG expression. Like in granulosa cells from FMR1 premutation carriers, FMRpolyG aggregates were found only in COV434 transfected with expended CGG repeats and the ability to express FMRpolyG. CONCLUSIONS:Corresponding with previous studies in FXTAS, we demonstrated accumulation of FMRpolyG in mural granulosa cells of FMR1 premutation carriers. We also suggest that following further investigation, the premutation transfected COV434 might be an appropriate model for RAN translation studies. Detecting FMRpolyG accumulation in folliculogenesis related cells supports previous observations and imply a possible common protein-mediated toxic mechanism for both FXPOI and FXTAS.

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Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation.

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