Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping, putative toxic mechanisms have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.

Repeat‐associated non‐ AUG translation in C9orf72‐ ALS / FTD is driven by neuronal excitation and stress

“…We examined the role of glutamate receptors in increasing non-AUG-dependent translation following excitotoxic stress by measuring DPR levels in the presence of glutamate receptor agonists and/or antagonists. Previous work has shown that neurons derived from C9orf72 NRE patient iPS cells show increased glutamate receptors (Shi et al, 2018), age-dependent glutamate sensitivity, and hyperactivity/hypoactivity (Donnelly et al, 2013;Sareen et al, 2013;Wainger et al, 2014;Devlin et al, 2015), and motor neuron excitotoxicity may be a primary mechanism that contributes to ALS disease pathogenesis (Starr & Sattler, 2018). Furthermore, HC levels increase moderately with age in the central nervous system, and ▸ Figure 2.…”

“…Previous work has shown that neurons derived from C9orf72 NRE patient iPS cells show increased glutamate receptors (Shi et al, 2018), age-dependent glutamate sensitivity, and hyperactivity/hypoactivity (Donnelly et al, 2013;Sareen et al, 2013;Wainger et al, 2014;Devlin et al, 2015), and motor neuron excitotoxicity may be a primary mechanism that contributes to ALS disease pathogenesis (Starr & Sattler, 2018). Previous work has shown that neurons derived from C9orf72 NRE patient iPS cells show increased glutamate receptors (Shi et al, 2018), age-dependent glutamate sensitivity, and hyperactivity/hypoactivity (Donnelly et al, 2013;Sareen et al, 2013;Wainger et al, 2014;Devlin et al, 2015), and motor neuron excitotoxicity may be a primary mechanism that contributes to ALS disease pathogenesis (Starr & Sattler, 2018).…”

“…Sustained depolarizations in excitable neurons can be triggered by aberrant extracellular accumulation of glutamate, which may lead to excitotoxic mechanisms of neuronal dysfunction and degeneration (Starr & Sattler, 2018). To test whether non-AUG-dependent translation of C9orf27 NRE is linked and could be modified by neuronal activity, we measured DPR levels in rat CN NES-mIFP in which we expressed channelrhodopsin-2 to optogenetically control their depolarization-repolarization activity.…”

FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for Gria2 mRNA processing

“…For instance, elevated levels of glutamate were detected in biological samples from ALS patients 5,49,50 . Cell death caused by glutamate and calcium dysregulation has also been documented in multiple animal and cellular models 1,2 ,5- 7,51 . The outcomes of this study shed new light on the excitotoxicity cascade and implicate, for the first time, a role for the ALS/FTD-linked protein FUS in this process.…”

“…8). In ALS, this process could be compromised as a result of dysregulated Gria2 editing and/or GluR2 expression 8,53 , particularly in motor neurons that rely heavily on AMPA receptor signaling 1,2 . The effect of FUS on dendritic Gria2 density following Glu excito (Fig.…”