Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase
Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/10/10/2745 |
| _version_ | 1827679917256474624 |
|---|---|
| author | Aitor Franco Lorea Velasco-Carneros Naiara Alvarez Natalia Orozco Fernando Moro Adelina Prado Arturo Muga |
| author_facet | Aitor Franco Lorea Velasco-Carneros Naiara Alvarez Natalia Orozco Fernando Moro Adelina Prado Arturo Muga |
| author_sort | Aitor Franco |
| collection | DOAJ |
| description | Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies. |
| first_indexed | 2024-03-10T06:39:48Z |
| format | Article |
| id | doaj.art-af47aa04988441bbb6c4d59e9dcde4e5 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T06:39:48Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-af47aa04988441bbb6c4d59e9dcde4e52023-11-22T17:48:27ZengMDPI AGCells2073-44092021-10-011010274510.3390/cells10102745Unzipping the Secrets of Amyloid Disassembly by the Human DisaggregaseAitor Franco0Lorea Velasco-Carneros1Naiara Alvarez2Natalia Orozco3Fernando Moro4Adelina Prado5Arturo Muga6Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, 48080 Bilbao, SpainNeurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.https://www.mdpi.com/2073-4409/10/10/2745neurodegenerationamyloidchaperonedisaggregase |
| spellingShingle | Aitor Franco Lorea Velasco-Carneros Naiara Alvarez Natalia Orozco Fernando Moro Adelina Prado Arturo Muga Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase Cells neurodegeneration amyloid chaperone disaggregase |
| title | Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase |
| title_full | Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase |
| title_fullStr | Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase |
| title_full_unstemmed | Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase |
| title_short | Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase |
| title_sort | unzipping the secrets of amyloid disassembly by the human disaggregase |
| topic | neurodegeneration amyloid chaperone disaggregase |
| url | https://www.mdpi.com/2073-4409/10/10/2745 |
| work_keys_str_mv | AT aitorfranco unzippingthesecretsofamyloiddisassemblybythehumandisaggregase AT loreavelascocarneros unzippingthesecretsofamyloiddisassemblybythehumandisaggregase AT naiaraalvarez unzippingthesecretsofamyloiddisassemblybythehumandisaggregase AT nataliaorozco unzippingthesecretsofamyloiddisassemblybythehumandisaggregase AT fernandomoro unzippingthesecretsofamyloiddisassemblybythehumandisaggregase AT adelinaprado unzippingthesecretsofamyloiddisassemblybythehumandisaggregase AT arturomuga unzippingthesecretsofamyloiddisassemblybythehumandisaggregase |