Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Type of study
Language
Publication year range
1.
PLoS Genet ; 19(9): e1010974, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37773959

ABSTRACT

Adenylosuccinate lyase deficiency is an ultrarare congenital metabolic disorder associated with muscle weakness and neurobehavioral dysfunction. Adenylosuccinate lyase is required for de novo purine biosynthesis, acting twice in the pathway at non-sequential steps. Genetic models can contribute to our understanding of the etiology of disease phenotypes and pave the way for development of therapeutic treatments. Here, we establish the first model to specifically study neurobehavioral aspects of adenylosuccinate lyase deficiency. We show that reduction of adsl-1 function in C. elegans is associated with a novel learning phenotype in a gustatory plasticity assay. The animals maintain capacity for gustatory plasticity, evidenced by a change in their behavior in response to cue pairing. However, their behavioral output is distinct from that of control animals. We link substrate accumulation that occurs upon adsl-1 deficiency to an unexpected perturbation in tyrosine metabolism and show that a lack of tyramine mediates the behavioral changes through action on the metabotropic TYRA-2 tyramine receptor. Our studies reveal a potential for wider metabolic perturbations, beyond biosynthesis of purines, to impact behavior under conditions of adenylosuccinate lyase deficiency.


Subject(s)
Adenylosuccinate Lyase , Adenylosuccinate Lyase/deficiency , Autistic Disorder , Caenorhabditis elegans Proteins , Purine-Pyrimidine Metabolism, Inborn Errors , Receptors, Biogenic Amine , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Adenylosuccinate Lyase/genetics , Adenylosuccinate Lyase/metabolism , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Caenorhabditis elegans Proteins/genetics
2.
Mol Genet Metab ; 140(3): 107686, 2023 11.
Article in English | MEDLINE | ID: mdl-37607437

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 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.


Subject(s)
Adenylosuccinate Lyase , Autistic Disorder , Purine-Pyrimidine Metabolism, Inborn Errors , Animals , Humans , Autistic Disorder/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Adenylosuccinate Lyase/genetics , Adenylosuccinate Lyase/metabolism , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Purine-Pyrimidine Metabolism, Inborn Errors/diagnosis , Phenotype , Purines
3.
Adv Exp Med Biol ; 1236: 225-244, 2020.
Article in English | MEDLINE | ID: mdl-32304075

ABSTRACT

Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.


Subject(s)
Disease Models, Animal , Metabolism, Inborn Errors , Animals , Gangliosidoses, GM2 , Humans , Rare Diseases/congenital , Sandhoff Disease , Tay-Sachs Disease
SELECTION OF CITATIONS
SEARCH DETAIL
...