Modeling Fragile X Syndrome in Drosophila

Abstract

Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5′-UTR of the gene. Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. This enables a much easier approach for FMR1 genetic studies. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. These studies have the potential to aid the discovery of pharmacological therapies for FXS.

Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

“…In humans, there are two paralogs of the FMR1 gene: FXR1 and FXR2. However, there is only one ortholog of FMR1 in Drosophila: dFMR1 [175]. The dFMR1 protein is expressed in the CNS, testis, and eye disc in larvae [176].…”

Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins

“…MR1 is a polysome-associated RNA binding protein required for the nervous system and ovary to develop and function normally in humans, mice, and Drosophila (1,2). Both tissues translationally control stored mRNAs associated with FMR1-containing ribonucleoprotein particles (RNPs) (3)(4)(5)(6), which suggests that FMR1 has a specific function in using stored mRNAs.…”

FMRP activates the translation of large autism/intellectual disability proteins and stimulates N-end rule E3 ligase Poe/UBR4 production within puromycin-sensitive RNP particles

“…FMRP plays an important and ancient role in the development and function of neurons, oocytes, and spermatocytes, where it is required in diverse animals ranging from Drosophila to humans (Hagerman et al 2017;Drozd et al 2018). Here we have addressed recent controversies regarding the action of FMRP on target mRNAs (Greenblatt and Spradling, 2018;Das Sharma et al 2019;Sawicki et al 2019).…”