Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease
Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy...
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2025-04-01
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| author | Diego Luis-Ravelo Felipe Fumagallo-Reading Alejandro Febles-Casquero Jonathan Lopez-Fernandez Daniel J. Marcellino Tomas Gonzalez-Hernandez |
| author_facet | Diego Luis-Ravelo Felipe Fumagallo-Reading Alejandro Febles-Casquero Jonathan Lopez-Fernandez Daniel J. Marcellino Tomas Gonzalez-Hernandez |
| author_sort | Diego Luis-Ravelo |
| collection | DOAJ |
| description | Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and <i>DRD2</i>- and <i>DRD3</i>-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and <i>Q23-DRD3</i>-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and <i>Q74-DRD3</i>-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and <i>DRD3</i>-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. |
| format | Article |
| id | doaj-art-ce70a02a36614feb8655693381574b83 |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-ce70a02a36614feb8655693381574b832025-08-20T02:24:47ZengMDPI AGCells2073-44092025-04-0114965210.3390/cells14090652Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s DiseaseDiego Luis-Ravelo0Felipe Fumagallo-Reading1Alejandro Febles-Casquero2Jonathan Lopez-Fernandez3Daniel J. Marcellino4Tomas Gonzalez-Hernandez5Institute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, SpainInstitute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, SpainDepartment of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38200 Tenerife, SpainInstitute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, SpainDepartment of Medical and Translational Biology, Umeå University, 901 87 Umeå, SwedenInstitute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, SpainHuntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and <i>DRD2</i>- and <i>DRD3</i>-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and <i>Q23-DRD3</i>-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and <i>Q74-DRD3</i>-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and <i>DRD3</i>-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients.https://www.mdpi.com/2073-4409/14/9/652dopamine receptorsHuntington’s diseaseneuroprotectionULK1mTORC1AMPK |
| spellingShingle | Diego Luis-Ravelo Felipe Fumagallo-Reading Alejandro Febles-Casquero Jonathan Lopez-Fernandez Daniel J. Marcellino Tomas Gonzalez-Hernandez Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease Cells dopamine receptors Huntington’s disease neuroprotection ULK1 mTORC1 AMPK |
| title | Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease |
| title_full | Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease |
| title_fullStr | Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease |
| title_full_unstemmed | Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease |
| title_short | Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington’s Disease |
| title_sort | dopamine receptor d3 induces transient mtorc1 dependent autophagy that becomes persistent ampk mediated and neuroprotective in experimental models of huntington s disease |
| topic | dopamine receptors Huntington’s disease neuroprotection ULK1 mTORC1 AMPK |
| url | https://www.mdpi.com/2073-4409/14/9/652 |
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