Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology
Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still el...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/15999 |
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| author | Topaz Kreiser Ilana Sogolovsky-Bard Dor Zaguri Shira Shaham-Niv Dana Laor Bar-Yosef Ehud Gazit |
| author_facet | Topaz Kreiser Ilana Sogolovsky-Bard Dor Zaguri Shira Shaham-Niv Dana Laor Bar-Yosef Ehud Gazit |
| author_sort | Topaz Kreiser |
| collection | DOAJ |
| description | Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease. |
| first_indexed | 2024-03-11T11:27:05Z |
| format | Article |
| id | doaj.art-27d7dbb7f8a74e14868efd6783631692 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:27:05Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-27d7dbb7f8a74e14868efd67836316922023-11-10T15:06:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124211599910.3390/ijms242115999Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease PathologyTopaz Kreiser0Ilana Sogolovsky-Bard1Dor Zaguri2Shira Shaham-Niv3Dana Laor Bar-Yosef4Ehud Gazit5The Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 6997801, IsraelThe Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 6997801, IsraelThe Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 6997801, IsraelThe Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 6997801, IsraelThe Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 6997801, IsraelThe Shmunis School of Biomedicine and Cancer Research, Tel Aviv University, Tel Aviv 6997801, IsraelInborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease.https://www.mdpi.com/1422-0067/24/21/15999BCAAsself-assemblyamyloid-like structuresmetabolite amyloidsmetabolostasisMSUD pathology |
| spellingShingle | Topaz Kreiser Ilana Sogolovsky-Bard Dor Zaguri Shira Shaham-Niv Dana Laor Bar-Yosef Ehud Gazit Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology International Journal of Molecular Sciences BCAAs self-assembly amyloid-like structures metabolite amyloids metabolostasis MSUD pathology |
| title | Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology |
| title_full | Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology |
| title_fullStr | Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology |
| title_full_unstemmed | Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology |
| title_short | Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology |
| title_sort | branched chain amino acid assembly into amyloid like fibrils provides a new paradigm for maple syrup urine disease pathology |
| topic | BCAAs self-assembly amyloid-like structures metabolite amyloids metabolostasis MSUD pathology |
| url | https://www.mdpi.com/1422-0067/24/21/15999 |
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