Reference - Detail
| RRC ID | 76120 |
|---|---|
| Author | Barker E, Morgan A, Barclay JW. |
| Title | A Caenorhabditis elegans model of autosomal dominant adult-onset neuronal ceroid lipofuscinosis identifies ethosuximide as a potential therapeutic. |
| Journal | Hum Mol Genet |
| Abstract |
Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is a rare neurodegenerative disorder characterized by progressive dementia and premature death. Four ANCL-causing mutations have been identified, all mapping to the DNAJC5 gene that encodes cysteine string protein α (CSPα). Here, using Caenorhabditis elegans, we describe an animal model of ANCL in which disease-causing mutations are introduced into their endogenous chromosomal locus, thereby mirroring the human genetic disorder. This was achieved through CRISPR/Cas9-mediated gene editing of dnj-14, the C. elegans ortholog of DNAJC5. The resultant homozygous ANCL mutant worms exhibited reduced lifespans and severely impaired chemotaxis, similar to isogenic dnj-14 null mutants. Importantly, these phenotypes were also seen in balanced heterozygotes carrying one wild-type and one ANCL mutant dnj-14 allele, mimicking the heterozygosity of ANCL patients. We observed a more severe chemotaxis phenotype in heterozygous ANCL mutant worms compared with haploinsufficient worms lacking one copy of CSP, consistent with a dominant-negative mechanism of action. Additionally, we provide evidence of CSP haploinsufficiency in longevity, as heterozygous null mutants exhibited significantly shorter lifespan than wild-type controls. The chemotaxis phenotype of dnj-14 null mutants was fully rescued by transgenic human CSPα, confirming the translational relevance of the worm model. Finally, a focused compound screen revealed that the anti-epileptic drug ethosuximide could restore chemotaxis in dnj-14 ANCL mutants to wild-type levels. This suggests that ethosuximide may have therapeutic potential for ANCL and demonstrates the utility of this C. elegans model for future larger-scale drug screening. |
| Volume | 32(11) |
| Pages | 1772-1785 |
| Published | 2023-5-18 |
| DOI | 10.1093/hmg/ddac263 |
| PII | 6772468 |
| PMID | 36282524 |
| PMC | PMC10196665 |
| MeSH | Adult Animals Animals, Genetically Modified Caenorhabditis elegans* / genetics Ethosuximide / pharmacology Ethosuximide / therapeutic use Humans Mutation Neuronal Ceroid-Lipofuscinoses* / drug therapy Neuronal Ceroid-Lipofuscinoses* / genetics Neuronal Ceroid-Lipofuscinoses* / metabolism |
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| Total number of mentions | 3 |
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| Resource | |
| C.elegans | tm3223 FX30236 |