The DOI matches its Crossref record; 209 of the 211 references it cites were found in a registry or an index.
Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD
Open accessAbstract
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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“The combination of NPTX2 (representing synaptic plasticity [35]), NfL (marker for overall neurodegeneration [60, 61]), and GFAP (depicting astrogliosis [62]) reflects the complexity of pathological mechanisms involved in neurodegenerative disorders and FTD in particular [63–66]”
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C9ORF72: What It Is, What It Does, and Why It Matters
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Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress
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Metadata
- 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)
- PMC
- PMC5997509
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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