Understanding and reversing large protein underproduction in fragile X–associated conditions
- Awarded: 2021
- Award Type: Bridge to Independence
- Award #: 653068
In order for the brain to carry out its complex functions, gene expression must be precisely controlled at the levels of transcription and translation. Neurons in particular rely heavily on translational regulation. This is because mRNAs encoding synaptic proteins are transported and translated at a distance from the nucleus. Mutations in the FMR1 gene result in loss of function of an important translation factor, FMRP, and lead to fragile X syndrome, which is the most common heritable cause of intellectual disability and autism spectrum disorder (ASD).
FMRP is an RNA-binding protein which preferentially binds to long mRNAs and facilitates the translation of large proteins, many of which are encoded by ASD risk genes1. This suggests that the FMRP system could be a therapeutic target for the treatment of a variety of ASD subtypes that are caused by haploinsufficiency of FMRP targets. However, lack of knowledge of the mechanism of FMRP-dependent translation has limited the ability to design therapeutic agents reversing translation changes in FMRP-deficient neurons.
To address this issue, Ethan Greenblatt and his colleagues are using a novel model of translational control, mature Drosophila oocytes, to understand the mechanism of FMRP-dependent translation and to identify suppressors of FMRP-related defects.2 Mature oocytes are advantageous for the study of translational control since they are transcriptionally quiescent and rely entirely on ongoing translation of stored mRNAs.
Greenblatt’s team is currently using the oocyte system to understand the role of abundant RNA granules known as P bodies in FMRP-dependent translation, define sequences in FMRP targets underlying its specificity, and develop novel diagnostics for the assessment of FMRP activity in situ.
The long-term goal of this work is to develop methods of fine-tuning large protein translation as a novel therapeutic route for the treatment of a number of ASD genetic subtypes.