Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia.

Simona Rossi,Mauro Cozzolino

doi:10.3390/cells10113005

Abstract

Amyotrophic Lateral Sclerosis is a neurological disease that primarily affects motor neurons in the cortex, brainstem, and spinal cord. The process that leads to motor neuron degeneration is strongly influenced by non-motor neuronal events that occur in a variety of cell types. Among these, neuroinflammatory processes mediated by activated astrocytes and microglia play a relevant role. In recent years, it has become clear that dysregulation of essential steps of RNA metabolism, as a consequence of alterations in RNA-binding proteins (RBPs), is a central event in the degeneration of motor neurons. Yet, a causal link between dysfunctional RNA metabolism and the neuroinflammatory processes mediated by astrocytes and microglia in ALS has been poorly defined. In this review, we will discuss the available evidence showing that RBPs and associated RNA processing are affected in ALS astrocytes and microglia, and the possible mechanisms involved in these events.

Highlights

Amyotrophic Lateral Sclerosis (ALS) is a disease of motor neurons and neighbouring non-neuronal cells
We want to provide an overview of what has been described so far about a possible role of reactive microglia and astrocytes in ALS linked to TDP-43, FUS, and C9orf72 mutations, and how dysfunctional RNA-binding proteins (RBPs) and associated RNA processing might be involved in these events
Glutamate receptor GLT1 expression in astrocytes and the consequent clearance of extracellular glutamate is diminished in mice knockout for FMRP [164]. This is due to a decreased expression of astroglial Gq-coupled metabotropic glutamate receptor mGluR5, whose mRNA is normally bound by FMRP and whose translation is impaired by the loss of FMRP. This is in contrast with the established role of FMRP as a translation inhibitor, these findings suggest the possibility, that needs to be demonstrated, that even in astrocytes an altered FMRP signalling by mutant ALS RBPs might affect local protein translation, which occurs in the distal, astrocyte peri-synaptic processes [165]

Summary

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a disease of motor neurons and neighbouring non-neuronal cells. Decreased neuronal cell viability can be caused by conditioned medium from cultured mouse and human astrocytes lac3koifn1g8 TDP-43 expression [54], expressing mutant forms of TDP-43 [55], FUS [56], and C9orf72 [57], or even overexpressing wild-type FUS [58], which is known to cause ALS pathology iTnDpPa-t4i3en[t5s5[]5, 9F,U60S],[5a6n]d, awnidldC-t9yoprfe7T2D[5P7-]4, 3or[4e8v]e. Conditioned medium from mouse astrocytes expressing a mutant (R521G) FUS affects the expression levels of AMPA receptor subunits GluA1 and GluA2 in cultured motor neurons, leading, in this case, to excitotoxic damage [56] Both the expression of the wild-type form or different mutant variants of TDP-43 and the reduction of TBPH in Drosophila glial cells result in alterations in neuromuscular junction morphology, associated with defective synaptic signals and locomotor dysfunction [48,70,71]. Much further work will be needed to resolve the issue, several observations, that will be summarized in the following paragraphs, have started to provide answers to these questions

TDP-43 and FUS

C9orf72

The Contribution of RNA Dysmetabolism to Neuroinflammation in ALS

Alternative Splicing in Reactive ALS Glia

Conclusions