TY - JOUR
T1 - A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology
AU - Fenton, Adam R.
AU - Janowitz, Haley N.
AU - Franklin, Latisha P.
AU - Young, Riley G.
AU - Moro, Corinna A.
AU - DeGennaro, Michael V.
AU - McReynolds, Melanie R.
AU - Wang, Wenqing
AU - Hanna-Rose, Wendy
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/11
Y1 - 2023/11
N2 - 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 bi-functional 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.
AB - 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 bi-functional 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.
UR - http://www.scopus.com/inward/record.url?scp=85168117445&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168117445&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2023.107686
DO - 10.1016/j.ymgme.2023.107686
M3 - Article
C2 - 37607437
AN - SCOPUS:85168117445
SN - 1096-7192
VL - 140
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 3
M1 - 107686
ER -