The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses
Summary: The loss of cerebellar Purkinje cells is a hallmark of neurodegenerative movement disorders, but the mechanisms remain enigmatic. We show that endocytic adaptor protein complex 2 (AP-2) is crucial for Purkinje cell survival. Using mouse genetics, viral tracing, calcium imaging, and kinemati...
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000270 |
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| author | Marianna Tolve Janine Tutas Ebru Özer-Yildiz Ines Klein Anne Petzold Veronika J. Fritz Melina Overhoff Quinn Silverman Ellie Koletsou Filip Liebsch Guenter Schwarz Tatiana Korotkova Silvana Valtcheva Graziana Gatto Natalia L. Kononenko |
| author_facet | Marianna Tolve Janine Tutas Ebru Özer-Yildiz Ines Klein Anne Petzold Veronika J. Fritz Melina Overhoff Quinn Silverman Ellie Koletsou Filip Liebsch Guenter Schwarz Tatiana Korotkova Silvana Valtcheva Graziana Gatto Natalia L. Kononenko |
| author_sort | Marianna Tolve |
| collection | DOAJ |
| description | Summary: The loss of cerebellar Purkinje cells is a hallmark of neurodegenerative movement disorders, but the mechanisms remain enigmatic. We show that endocytic adaptor protein complex 2 (AP-2) is crucial for Purkinje cell survival. Using mouse genetics, viral tracing, calcium imaging, and kinematic analysis, we demonstrate that loss of the AP-2 μ subunit in Purkinje cells leads to early-onset ataxia and progressive degeneration. Synaptic dysfunction, marked by an overrepresentation of parallel fibers (PFs) over climbing fibers (CFs), precedes Purkinje cell loss. Mechanistically, AP-2 interacts with the PF-enriched protein GRID2IP, and its loss triggers GRID2IP degradation and glutamate δ2 receptor (GLURδ2) accumulation, leading to an excess of PFs while CFs are reduced. The overrepresentation of PFs increases Purkinje cell network activity, which is mitigated by enhancing glutamate clearance with ceftriaxone. These findings highlight the role of AP-2 in regulating GRID2IP levels in Purkinje cells to maintain PF-CF synaptic balance and prevent motor dysfunction. |
| format | Article |
| id | doaj-art-9372759a5f7248ff8a5b81dc5399cd20 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-9372759a5f7248ff8a5b81dc5399cd202025-02-07T04:47:27ZengElsevierCell Reports2211-12472025-02-01442115256The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapsesMarianna Tolve0Janine Tutas1Ebru Özer-Yildiz2Ines Klein3Anne Petzold4Veronika J. Fritz5Melina Overhoff6Quinn Silverman7Ellie Koletsou8Filip Liebsch9Guenter Schwarz10Tatiana Korotkova11Silvana Valtcheva12Graziana Gatto13Natalia L. Kononenko14Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyNeurology Department, University Hospital of Cologne, University of Cologne, Cologne, GermanyInstitute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyNeurology Department, University Hospital of Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, GermanyInstitute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, GermanyInstitute of Biochemistry, Department of Chemistry, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Institute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyInstitute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanyNeurology Department, University Hospital of Cologne, University of Cologne, Cologne, GermanyCologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Institute of Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany; Corresponding authorSummary: The loss of cerebellar Purkinje cells is a hallmark of neurodegenerative movement disorders, but the mechanisms remain enigmatic. We show that endocytic adaptor protein complex 2 (AP-2) is crucial for Purkinje cell survival. Using mouse genetics, viral tracing, calcium imaging, and kinematic analysis, we demonstrate that loss of the AP-2 μ subunit in Purkinje cells leads to early-onset ataxia and progressive degeneration. Synaptic dysfunction, marked by an overrepresentation of parallel fibers (PFs) over climbing fibers (CFs), precedes Purkinje cell loss. Mechanistically, AP-2 interacts with the PF-enriched protein GRID2IP, and its loss triggers GRID2IP degradation and glutamate δ2 receptor (GLURδ2) accumulation, leading to an excess of PFs while CFs are reduced. The overrepresentation of PFs increases Purkinje cell network activity, which is mitigated by enhancing glutamate clearance with ceftriaxone. These findings highlight the role of AP-2 in regulating GRID2IP levels in Purkinje cells to maintain PF-CF synaptic balance and prevent motor dysfunction.http://www.sciencedirect.com/science/article/pii/S2211124725000270CP: Neuroscience |
| spellingShingle | Marianna Tolve Janine Tutas Ebru Özer-Yildiz Ines Klein Anne Petzold Veronika J. Fritz Melina Overhoff Quinn Silverman Ellie Koletsou Filip Liebsch Guenter Schwarz Tatiana Korotkova Silvana Valtcheva Graziana Gatto Natalia L. Kononenko The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses Cell Reports CP: Neuroscience |
| title | The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses |
| title_full | The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses |
| title_fullStr | The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses |
| title_full_unstemmed | The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses |
| title_short | The endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses |
| title_sort | endocytic adaptor ap 2 maintains purkinje cell function by balancing cerebellar parallel and climbing fiber synapses |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000270 |
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