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Journal article
A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology
MOLECULAR GENETICS AND METABOLISM, v 140(3), 107686
Nov 2023
PMID: 37607437
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the activity of the bifunctional purine biosynthetic enzyme adenylosuccinate lyase (ADSL). Mutations in human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of ASLD is known, the molecular mechanisms driving phenotypic outcome are not. Here, we characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in Caenorhabditis elegans. We demonstrate that adsl-1 function contributes to regulation of spontaneous locomotion, that adsl-1 functions acutely for proper mobility, and that aspects of adsl-1-related dysfunction are reversible. Using pharmacological supplementation, we correlate phenotypes with distinct metabolic perturbations. The neuromuscular defect correlates with accumulation of a purine biosynthetic intermediate whereas reproductive deficiencies can be ameliorated by purine supplementation, indicating differing molecular mechanisms behind the phenotypes. Because purine metabolism is highly conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial.
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- Title
- A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology
- Publication Details
- MOLECULAR GENETICS AND METABOLISM, v 140(3), 107686
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE; SAN DIEGO
- Grant note
- We thank A. Patterson and P. Smith in the Penn State Metabolomics Core Facility for technical assistance and advice. tm alleles were provided by the Mitani laboratory through the National Bio-Resource Project of the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan. Other strains were provided by the Caenorhabditis Genetics Center, which is funded by National Institutes of Health Office of Research Infrastructure Programs (Grant P40 OD010440). We acknowledge a J. Lloyd Huck Biotechnology Mini-grant from the Huck Institutes of the Life Science for support for this work. This work was supported by the National Institutes of Health [#R03NS096451].
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001061583700001
- Scopus ID
- 2-s2.0-85168117445
- Other Identifier
- 991021861189904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Endocrinology & Metabolism
- Genetics & Heredity
- Medicine, Research & Experimental