Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast
Protein misfolding, aggregation, and accumulation cause neurodegenerative disorders. One such disorder, Huntington’s disease, is caused by an increased number of glutamine-encoding trinucleotide repeats CAG in the first exon of the huntingtin (HTT) gene. Mutant proteins of Htt exon 1 with polyglutam...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Autophagy Reports |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/27694127.2023.2236407 |
| _version_ | 1797685720978030592 |
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| author | Austin Folger Chuan Chen Marie-Helene Kabbaj Karina Frey Yanchang Wang |
| author_facet | Austin Folger Chuan Chen Marie-Helene Kabbaj Karina Frey Yanchang Wang |
| author_sort | Austin Folger |
| collection | DOAJ |
| description | Protein misfolding, aggregation, and accumulation cause neurodegenerative disorders. One such disorder, Huntington’s disease, is caused by an increased number of glutamine-encoding trinucleotide repeats CAG in the first exon of the huntingtin (HTT) gene. Mutant proteins of Htt exon 1 with polyglutamine expansion are prone to aggregation and form pathological inclusion bodies in neurons. Extensive studies have shown that misfolded proteins are cleared by the ubiquitin-proteasome system or autophagy to alleviate their cytotoxicity. Misfolded proteins can form small soluble aggregates or large insoluble inclusion bodies. Previous works have elucidated the role of autophagy in the clearance of misfolded protein aggregates, but autophagic clearance of inclusion bodies remains poorly characterised. Here we use mutant Htt exon 1 with 103 polyglutamine (Htt103QP) as a model substrate to study the autophagic clearance of inclusion bodies in budding yeast. We found that the core autophagy-related proteins were required for Htt103QP inclusion body autophagy. Moreover, our evidence indicates that the autophagy of Htt103QP inclusion bodies is selective. Interestingly, Cue5/Tollip, a known autophagy receptor for aggrephagy, is dispensable for this inclusion body autophagy. From the known selective autophagy receptors in budding yeast, we identified three that are essential for inclusion body autophagy. Amyloid beta peptide (Aβ42) is a major component of amyloid plaques found in Alzheimer’s disease brains. Interestingly, a similar selective autophagy pathway contributes to the clearance of Aβ42 inclusion bodies in budding yeast. Therefore, our results reveal a novel autophagic pathway specific for inclusion bodies associated with neurodegenerative diseases, which we have termed IBophagy. |
| first_indexed | 2024-03-12T00:55:23Z |
| format | Article |
| id | doaj.art-a5e6406a761c4f5fb9b6fb5f8a0a5d84 |
| institution | Directory Open Access Journal |
| issn | 2769-4127 |
| language | English |
| last_indexed | 2024-03-12T00:55:23Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj.art-a5e6406a761c4f5fb9b6fb5f8a0a5d842023-09-14T13:24:41ZengTaylor & Francis GroupAutophagy Reports2769-41272023-12-012110.1080/27694127.2023.22364072236407Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeastAustin Folger0Chuan Chen1Marie-Helene Kabbaj2Karina Frey3Yanchang Wang4College of Medicine, Florida State UniversityHebei UniversityCollege of Medicine, Florida State UniversityFlorida State University (undergraduate student)College of Medicine, Florida State UniversityProtein misfolding, aggregation, and accumulation cause neurodegenerative disorders. One such disorder, Huntington’s disease, is caused by an increased number of glutamine-encoding trinucleotide repeats CAG in the first exon of the huntingtin (HTT) gene. Mutant proteins of Htt exon 1 with polyglutamine expansion are prone to aggregation and form pathological inclusion bodies in neurons. Extensive studies have shown that misfolded proteins are cleared by the ubiquitin-proteasome system or autophagy to alleviate their cytotoxicity. Misfolded proteins can form small soluble aggregates or large insoluble inclusion bodies. Previous works have elucidated the role of autophagy in the clearance of misfolded protein aggregates, but autophagic clearance of inclusion bodies remains poorly characterised. Here we use mutant Htt exon 1 with 103 polyglutamine (Htt103QP) as a model substrate to study the autophagic clearance of inclusion bodies in budding yeast. We found that the core autophagy-related proteins were required for Htt103QP inclusion body autophagy. Moreover, our evidence indicates that the autophagy of Htt103QP inclusion bodies is selective. Interestingly, Cue5/Tollip, a known autophagy receptor for aggrephagy, is dispensable for this inclusion body autophagy. From the known selective autophagy receptors in budding yeast, we identified three that are essential for inclusion body autophagy. Amyloid beta peptide (Aβ42) is a major component of amyloid plaques found in Alzheimer’s disease brains. Interestingly, a similar selective autophagy pathway contributes to the clearance of Aβ42 inclusion bodies in budding yeast. Therefore, our results reveal a novel autophagic pathway specific for inclusion bodies associated with neurodegenerative diseases, which we have termed IBophagy.http://dx.doi.org/10.1080/27694127.2023.2236407autophagyibophagymutant huntingtinaβ42inclusion body |
| spellingShingle | Austin Folger Chuan Chen Marie-Helene Kabbaj Karina Frey Yanchang Wang Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast Autophagy Reports autophagy ibophagy mutant huntingtin aβ42 inclusion body |
| title | Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast |
| title_full | Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast |
| title_fullStr | Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast |
| title_full_unstemmed | Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast |
| title_short | Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast |
| title_sort | neurodegenerative disease associated inclusion bodies are cleared by selective autophagy in budding yeast |
| topic | autophagy ibophagy mutant huntingtin aβ42 inclusion body |
| url | http://dx.doi.org/10.1080/27694127.2023.2236407 |
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