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Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis
Abstract
Objective: To define the role that repeat expansions of a GGGGCC hexanucleotide sequence of the C9orf72 gene play in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC9orf72) leads to abnormalities in neuronal development. Methods: C9orf72 mRNA levels were quantified in brain and lymphoblasts derived from FTLD and ALS/FTLD patients and in zebrafish. Knockdown of the zC9orf72 was performed using 2 specific antisense morpholino oligonucleotides to block transcription. Quantifications of spontaneous swimming and tactile escape response, as well as measurements of axonal projections from the spinal cord, were performed. Results: Significantly decreased expression of C9orf72 transcripts in brain and lymphoblasts was found in sporadic FTLD and ALS/FTLD patients with normal‐size or expanded hexanucleotide repeats. The zC9orf72 is selectively expressed in the developing nervous system at developmental stages. Loss of function of the zC9orf72 transcripts causes both behavioral and cellular deficits related to locomotion without major morphological abnormalities. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. Interpretation: Our results indicate C9orf72 haploinsufficiency could be a contributing factor in the spectrum of ALS/FTLD neurodegenerative disorders. Loss of function of the zebrafish orthologue of zC9orf72 expression in zebrafish is associated with axonal degeneration of motor neurons that can be rescued by expressing human C9orf72 mRNA, highlighting the specificity of the induced phenotype. These results reveal a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. Ann Neurol 2013;74:180–187
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“Deletion of the zebrafish and C. elegans homologs of C9orf72 results in impaired locomotion and motor axon degeneration [182,183], implying that the C9orf72 protein is essential for motor neuron function and survival in these systems.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [182]
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Metadata
- Authors
- Ciura, S., Lattante, S., Le Ber, I., Latouche, M., Tostivint, H., Brice, A., & Kabashi, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Research Center of the Institute for Brain and Spinal Cord CRICM National Institute of Health and Medical Research ‐ Inserm UMR_S975 National Center for Scientific Reseach CNRS UMR_7225 Pierre and Marie Curie University UPMC Paris 6 F‐75013 Paris France
- Corresponding author
- Kabashi, Edor
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2013-08
- Volume
- 74
- Issue
- 2
- Pages
- 180-187
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2158949580
- Cited by
- 333
- References
- 31
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 11 · 2023: 14 · 2022: 16 · 2021: 29 · 2020: 31 · 2019: 23 · 2018: 39 · 2017: 31 · 2016: 42 · 2015: 32 · 2014: 36 · 2013: 14
- FWCI
- 26.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- AIRUS (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- C9orf72, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, GGGGCC repeat expansion, haploinsufficiency, zebrafish model, motor impairment, axonal degeneration, motor neurons, locomotor activity, morpholino knockdown, neurodegeneration
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Behavior, Animal, Disease Models, Animal, Humans, Lymphocytes, Motor Activity, Proteins, Zebrafish, Zebrafish Proteins, Frontotemporal Lobar Degeneration
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