Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD

“…Dysfunction of synapses is a common feature in many neurodegenerative diseases, including C9ALS/FTD [ 30 , 31 , 56 , 57 ]. Given the interaction of C9orf72 with synapsin at synapses (Fig.…”

“…The data presented here show that C9orf72 haploinsufficiency per se can cause neuronal damage independent of gain-of-function mechanisms. Synaptic dysfunction and loss are a recurring theme in ALS/FTD, including in non-C9orf72 related familial and sporadic forms of the disease, and appear to precede neurodegeneration [ 31 , 56 , 57 , 71 ]. Advanced stages of ALS/FTD, including in C9orf72 repeat expansion patients, are associated with synaptic loss, where the extent of loss correlates with the clinical severity of cognitive impairments [ 31 ].…”

“…Synaptic dysfunction and degeneration are inherent pathophysiological hallmarks of neurodegenerative diseases, including ALS/FTD [ 30 , 56 , 57 ]. Here we have identified the synapsin protein family as novel interactors of C9orf72.…”

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

“…Intriguingly, using two complementary methods, namely two-photon calcium imaging and high-density Neuropixels recording, we observed hyperexcitability in polyGR mice in superficial cortical layers, which are affected in FTD, but not deeper layer 5 neurons which are vulnerable in ALS. Further research is needed to parse this difference and its relevance, but it is noteworthy that cortical hyperexcitability is well described in both C9 and non- C9 ALS/FTD patients 39 , indicating that new mechanistic insights into this early patient-relevant phenotype can be gained by future investigations in our polyGR mice. It is also interesting that only polyGR but not polyPR mice showed this phenotype.…”

Chorea: An Update on Genetics

“…It is of note that neuronal malfunction is present before degeneration and is suggested to be linked to changes in synaptic and network properties. Neurodegeneration is probably due to haploinsufficiency of the protein and to aberrant protein species [52].…”