FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game

Abstract

Fragile X mental retardation protein (FMRP) is an RNA binding protein (RBP) whose absence is essentially associated to Fragile X Syndrome (FXS). As an RNA Binding Protein (RBP), FMRP is able to bind and recognize different RNA structures and the control of specific mRNAs is important for neuronal synaptic plasticity. Perturbations of this pathway have been associated with the autistic spectrum. One of the FMRP partners is the APP mRNA, the main protagonist of Alzheimer’s disease (AD), thereby regulating its protein level and metabolism. Therefore FMRP is associated to two neurodevelopmental and age-related degenerative conditions, respectively FXS and AD. Although these pathologies are characterized by different features, they have been reported to share a number of common molecular and cellular players. The aim of this review is to describe the double-edged sword of FMRP in autism and AD, possibly allowing the elucidation of key shared underlying mechanisms and neuronal circuits. As an RBP, FMRP is able to regulate APP expression promoting the production of amyloid β fragments. Indeed, FXS patients show an increase of amyloid β load, typical of other neurological disorders, such as AD, Down syndrome, Parkinson’s Disease, etc. Beyond APP dysmetabolism, the two neurodegenerative conditions share molecular targets, brain circuits and related cognitive deficits. In this review, we will point out the potential common neuropathological pattern which needs to be addressed and we will hopefully contribute to clarifying the complex phenotype of these two neurorological disorders, in order to pave the way for a novel, common disease-modifying therapy.

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

“…Changes in synapse number and behavior could theoretically be linked to the efficacy of Ro + CGP combinational therapies to rescue chloride ion imbalances via FMRP. Reduced FMRP levels have been shown in the neurological disorders discussed in this review ( 184 – 188 ), but also several other disorders not mentioned such as major depressive disorder ( 189 ), Parkinson’s disease ( 190 ), epilepsy ( 185 , 191 ), and schizophrenia ( 192 , 193 ). Furthermore, a novel combinational therapy antagonizing both NMDARs and GABA B Rs could universally alleviate pathologies and symptoms across various diseases.…”

Prediction of Translational Regulation by Network Interaction in Synaptic Plasticity Induced with Centella asiatica

“…mTOR signaling has been implicated in AD, displaying a dual role in neurodegenerative disease. It has been found to increase during neurofibrillary degeneration characterized by tau phosphorylation, while an opposing effect has also been described [ 19 ].…”

“…FMRP also plays a role in regulating specific mRNA expression around synapses in response to external stimuli. The absence of this protein causes abnormal translational expression, leading to alterations in synaptic plasticity [ 19 ]. Inhibition of FMRP binding to BC-1 noncoding RNA was shown to suppress APP translation and restore amyloid beta levels.…”

SERBP1 interacts with PARP1 and is present in PARylation-dependent protein complexes regulating splicing, cell division, and ribosome biogenesis

“…Not only was this interaction validated, but we also determined that SERBP1 associates with FMRP partner proteins FXR1 and FXR2. FMRP is the main driver of Fragile X mental retardation but has also been linked to Alzheimer's disease and autism (118,119). FMRP is a complex protein that binds different RNA motifs (including G4s) and regulates translation, splicing, RNA editing, and miRNA function, affecting synapse formation and plasticity, stress granule formation, channel signaling, and differentiation (120)(121)(122)(123).…”