Cited by 79Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsGenetic Neurodegenerative Diseases

Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

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Starr, Alexander, Sattler, Rita·2018·Brain Research

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.

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  1. Geevasinga N 2015c Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis JAMA Neurol 1 7 PMC4707047 26348842
  2. Rothstein JD 1991 Excitatory amino acids in ALS: an update Ann. Neurol 30 224 225 1680305

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Authors
Starr, A., & Sattler, R.
Affiliations
Barrow Neurological Institute (US)
Corresponding author
Sattler, Rita
Venue
Brain Research
Publisher
Elsevier BV
Published
2018-08
Volume
1693
Issue
Pt A
Pages
98-108
ISSN
0006-8993 (ISSN-L)
OpenAlex
W2790884408
Cited by
78
References
211
Citations by year
2026: 2 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 21 · 2021: 15 · 2020: 10 · 2019: 5 · 2018: 3
FWCI
1.30
Type
journal article
Language
en
Open access
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Fogarty International Center
  • National Institute of Neurological Disorders and Stroke (R01NS085207)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, synaptic dysfunction, neuronal excitability, excitotoxicity, RNA-binding proteins, hexanucleotide repeat expansion, dipeptide repeat proteins, repeat-associated non-ATG translation, RNA foci, neuromuscular junction, synaptogenesis, motor neurons, therapeutic target
MeSH terms
C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Humans, Motor Neurons, Mutation, RNA, Synapses, RNA-Binding Proteins, Frontotemporal Dementia

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