ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects

Abstract

The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shrub mRNA (human Chmp4) to repress Shrub expression, causing overexpression during the disease state early-use critical period. The FXS hallmark is synaptic overelaboration causing circuit hyperconnectivity. Testing innervation of a central brain learning/memory center, we found FMRP loss and Shrub overexpression similarly increase connectivity. The ESCRT-III core protein Shrub has a central role in endosome-to-multivesicular body membrane trafficking, with synaptic requirements resembling FMRP. Consistently, we found FMRP loss and Shrub overexpression similarly elevate endosomes and result in the arrested accumulation of enlarged intraluminal vesicles within synaptic boutons. Importantly, genetic correction of Shrub levels in the FXS model prevents synaptic membrane trafficking defects and strongly restores innervation. These results reveal a new molecular mechanism underpinning the FXS disease state.

Expression of mutant CHMP2B linked to neurodegeneration in humans disrupts circadian rhythms inDrosophila

“…Second, mutations in CHMP2B/ESCRTs disrupt the physiology of circadian neurons due to misregulation of non‐circadian proteins thereby indirectly causing circadian rhythm phenotypes. This notion is supported by findings in the Drosophila model of Fragile X syndrome (FXS), where loss of Drosophila Fragile X Mental Retardation Protein (dFMRP) causes circadian rhythm deficits because of defective synaptic plasticity of circadian neurons . Interestingly, dFMRP is a negative regulator of Shrub—an ESCRT‐III component.…”

“…This notion is supported by findings in the Drosophila model of Fragile X syndrome (FXS), where loss of Drosophila Fragile X Mental Retardation Protein (dFMRP) causes circadian rhythm deficits because of defective synaptic plasticity of circadian neurons. 46,47 Interestingly, dFMRP is a negative regulator of Shrub-an ESCRT-III component. Therefore, circadian deficits in the FXS fly model due to loss of dFMRP can be attributed to endosomal-lysosomal defects due to Shrub gain-of-function.…”

Activity-Dependent Remodeling ofDrosophilaOlfactory Sensory Neuron Brain Innervation during an Early-Life Critical Period

“…Critical periods are discrete developmental time windows when the brain is especially susceptible to modification by sensory stimuli. Since the classical visual cortex work by Hubel and Wiesel (1970), enormous progress has been made in understanding critical period refinement (LeVay et al, 1980;Hensch, 2005;Morishita et al, 2010) and how it goes awry in neurological diseases (Dölen et al, 2007;Contractor et al, 2015;Broadie, 2015, 2016;Golovin and Broadie, 2016;Doll et al, 2017;Vita and Broadie, 2017). Typically, critical periods open with the onset of sensory experience and close after a defined period of refinement, during which neural circuitry is modified to better respond to the sensory environment (Hensch, 2005).…”

“…Western blots. Western blots were performed as reported (Vita and Broadie, 2017), with slight modifications. Staged animals were exposed to oil or EB as described above.…”

Suppressor of clathrin deficiency (Scd6)—An emerging RGG‐motif translation repressor

“…The idea that RGG‐motif translation repressors could affect intracellular trafficking by regulating relevant transcripts is also supported by observations related to FMRP. It negatively regulates translation of a component of the ESCRT (Endosomal Sorting Complexes Required for Transport) complex ensuring efficient endocytic membrane trafficking (Vita & Broadie, ). Interestingly, FMRP, despite being a translation repressor, has been reported to enhance translation of its targets in complex with other proteins and microRNAs (Fernandez et al, ; P. Kenny & Ceman, ; P. J. Kenny et al, ; Muddashetty, Kelic, Gross, Xu, & Bassell, ; Todd, Mack, & Malter, ).…”