PUBLICATION
C9ORF72 deficiency results in neurodegeneration in the zebrafish retina
- Authors
- Jaroszynska, N., Salzinger, A., Tsarouchas, T.M., Becker, C.G., Becker, T., Lyons, D.A., MacDonald, R.B., Keatinge, M.
- ID
- ZDB-PUB-240425-13
- Date
- 2024
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 44(25): (Journal)
- Registered Authors
- Becker, Catherina G., Becker, Thomas, Lyons, David A.
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- C9orf72 Protein*/genetics
- C9orf72 Protein*/metabolism
- Female
- Neurodegenerative Diseases/genetics
- Neurodegenerative Diseases/metabolism
- Neurodegenerative Diseases/pathology
- Proteins/genetics
- Proteins/metabolism
- Retina*/metabolism
- Retina*/pathology
- Retinal Degeneration/genetics
- Retinal Degeneration/metabolism
- Retinal Degeneration/pathology
- Spinal Cord/metabolism
- Spinal Cord/pathology
- Zebrafish*
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38658168 Full text @ J. Neurosci.
Citation
Jaroszynska, N., Salzinger, A., Tsarouchas, T.M., Becker, C.G., Becker, T., Lyons, D.A., MacDonald, R.B., Keatinge, M. (2024) C9ORF72 deficiency results in neurodegeneration in the zebrafish retina. The Journal of neuroscience : the official journal of the Society for Neuroscience. 44(25):.
Abstract
Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting loss of C9ORF72 function could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the adult female spinal cords revealed no appreciable neurodegenerative pathology such as loss of motor neurons, or increased levels of neuroinflammation. However, detailed examination of adult female c9orf72-/- retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Analysis of rod and cone cells within the photoreceptor layer showed a disturbance in their outer segment structure and rhodopsin mis-localisation from rod outer segments to their cell bodies and synaptic terminals. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.Significance statement Hexanucleotide expansions in the gene C9ORF72 are the most common cause of the Amyotrophic lateral sclerosis (ALS)/ Frontotemporal dementia (FTD) disease spectrum. The expansion reduces expression of C9ORF72 and so may play a role in neuronal loss. However, C9ORF72 loss of function has been comparatively understudied in vivo. Using the zebrafish as a model of C9ORF72 deficiency, we demonstrate that loss of C9ORF72 results in marked inflammation and neuronal loss in the aged adult zebrafish retina. Development of the retina is unaffected regardless of C9ORF72 status. This demonstrates that C9ORF72 loss of function can cause spontaneous neurodegeneration in vivo and highlights a novel role of C9ORF72 in retinal homeostasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping