Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS
Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neur...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000099 |
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| author | Valentina Naef Devid Damiani Rosario Licitra Maria Marchese Stefania Della Vecchia Matteo Baggiani Letizia Brogi Daniele Galatolo Silvia Landi Filippo Maria Santorelli |
| author_facet | Valentina Naef Devid Damiani Rosario Licitra Maria Marchese Stefania Della Vecchia Matteo Baggiani Letizia Brogi Daniele Galatolo Silvia Landi Filippo Maria Santorelli |
| author_sort | Valentina Naef |
| collection | DOAJ |
| description | Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish knock-out strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression. |
| format | Article |
| id | doaj-art-0d43663f5f264b31b301baf0b60f4d7a |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-0d43663f5f264b31b301baf0b60f4d7a2025-01-24T04:44:42ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106793Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACSValentina Naef0Devid Damiani1Rosario Licitra2Maria Marchese3Stefania Della Vecchia4Matteo Baggiani5Letizia Brogi6Daniele Galatolo7Silvia Landi8Filippo Maria Santorelli9Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy; Corresponding author.Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyNeurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyNeurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyNeurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyNeurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyBio@SNS, Department of Neurosciences, Scuola Normale Superiore, 56126 Pisa, ItalyNeurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, ItalyIstituto di Neuroscienze-CNR, Pisa, ItalyNeurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy; Corresponding author.Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish knock-out strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression.http://www.sciencedirect.com/science/article/pii/S0969996125000099ARSACSZebrafishRetina developmentRetinal abnormalitiesNeurological disorder |
| spellingShingle | Valentina Naef Devid Damiani Rosario Licitra Maria Marchese Stefania Della Vecchia Matteo Baggiani Letizia Brogi Daniele Galatolo Silvia Landi Filippo Maria Santorelli Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS Neurobiology of Disease ARSACS Zebrafish Retina development Retinal abnormalities Neurological disorder |
| title | Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS |
| title_full | Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS |
| title_fullStr | Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS |
| title_full_unstemmed | Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS |
| title_short | Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS |
| title_sort | modeling sacsin depletion in danio rerio offers new insight on retinal defects in arsacs |
| topic | ARSACS Zebrafish Retina development Retinal abnormalities Neurological disorder |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000099 |
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