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Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1

Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype....

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Autores principales: Barroso, Madalena, Gertzen, Marcus, Puchwein-Schwepcke, Alexandra F., Preisler, Heike, Sturm, Andreas, Reiss, Dunja D., Danecka, Marta K., Muntau, Ania C., Gersting, Søren W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487539/
https://www.ncbi.nlm.nih.gov/pubmed/37685964
http://dx.doi.org/10.3390/ijms241713158
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author Barroso, Madalena
Gertzen, Marcus
Puchwein-Schwepcke, Alexandra F.
Preisler, Heike
Sturm, Andreas
Reiss, Dunja D.
Danecka, Marta K.
Muntau, Ania C.
Gersting, Søren W.
author_facet Barroso, Madalena
Gertzen, Marcus
Puchwein-Schwepcke, Alexandra F.
Preisler, Heike
Sturm, Andreas
Reiss, Dunja D.
Danecka, Marta K.
Muntau, Ania C.
Gersting, Søren W.
author_sort Barroso, Madalena
collection PubMed
description Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability (p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype.
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spelling pubmed-104875392023-09-09 Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1 Barroso, Madalena Gertzen, Marcus Puchwein-Schwepcke, Alexandra F. Preisler, Heike Sturm, Andreas Reiss, Dunja D. Danecka, Marta K. Muntau, Ania C. Gersting, Søren W. Int J Mol Sci Article Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability (p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype. MDPI 2023-08-24 /pmc/articles/PMC10487539/ /pubmed/37685964 http://dx.doi.org/10.3390/ijms241713158 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barroso, Madalena
Gertzen, Marcus
Puchwein-Schwepcke, Alexandra F.
Preisler, Heike
Sturm, Andreas
Reiss, Dunja D.
Danecka, Marta K.
Muntau, Ania C.
Gersting, Søren W.
Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
title Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
title_full Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
title_fullStr Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
title_full_unstemmed Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
title_short Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1
title_sort glutaryl-coa dehydrogenase misfolding in glutaric acidemia type 1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487539/
https://www.ncbi.nlm.nih.gov/pubmed/37685964
http://dx.doi.org/10.3390/ijms241713158
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