Critical role for Piccolo in synaptic vesicle retrieval
Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysi...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2019-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/46629 |
| _version_ | 1811199616948895744 |
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| author | Frauke Ackermann Kay Oliver Schink Christine Bruns Zsuzsanna Izsvák F Kent Hamra Christian Rosenmund Craig Curtis Garner |
| author_facet | Frauke Ackermann Kay Oliver Schink Christine Bruns Zsuzsanna Izsvák F Kent Hamra Christian Rosenmund Craig Curtis Garner |
| author_sort | Frauke Ackermann |
| collection | DOAJ |
| description | Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to interact selectively with the zinc finger domains of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to developmental and psychiatric disorders. |
| first_indexed | 2024-04-12T01:50:27Z |
| format | Article |
| id | doaj.art-69ba1bf9b55043f083573480f4785083 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:50:27Z |
| publishDate | 2019-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-69ba1bf9b55043f083573480f47850832022-12-22T03:52:57ZengeLife Sciences Publications LtdeLife2050-084X2019-05-01810.7554/eLife.46629Critical role for Piccolo in synaptic vesicle retrievalFrauke Ackermann0https://orcid.org/0000-0003-3037-8672Kay Oliver Schink1https://orcid.org/0000-0002-5903-4059Christine Bruns2Zsuzsanna Izsvák3F Kent Hamra4Christian Rosenmund5https://orcid.org/0000-0002-3905-2444Craig Curtis Garner6German Center for Neurodegenerative Diseases e.V. (DZNE), Charité Medical University, Berlin, GermanyCenter for Cancer Biomedicine, University of Oslo, Norwegian Radium Hospital, Oslo, NorwayGerman Center for Neurodegenerative Diseases e.V. (DZNE), Charité Medical University, Berlin, GermanyMax-Delbrück Center for Molecular Medicine in the Helmholtz Society, Berlin, GermanyDepartment of Obstetrics and Gynecology, University of Texas Southwestern, Dallas, United StatesNeuroCure Cluster of Excellence, Neuroscience Research Center, Charité Medical University, Berlin, GermanyGerman Center for Neurodegenerative Diseases e.V. (DZNE), Charité Medical University, Berlin, GermanyLoss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to interact selectively with the zinc finger domains of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to developmental and psychiatric disorders.https://elifesciences.org/articles/46629synaptic vesiclesearly endosomesrecyclingRab5Piccolo |
| spellingShingle | Frauke Ackermann Kay Oliver Schink Christine Bruns Zsuzsanna Izsvák F Kent Hamra Christian Rosenmund Craig Curtis Garner Critical role for Piccolo in synaptic vesicle retrieval eLife synaptic vesicles early endosomes recycling Rab5 Piccolo |
| title | Critical role for Piccolo in synaptic vesicle retrieval |
| title_full | Critical role for Piccolo in synaptic vesicle retrieval |
| title_fullStr | Critical role for Piccolo in synaptic vesicle retrieval |
| title_full_unstemmed | Critical role for Piccolo in synaptic vesicle retrieval |
| title_short | Critical role for Piccolo in synaptic vesicle retrieval |
| title_sort | critical role for piccolo in synaptic vesicle retrieval |
| topic | synaptic vesicles early endosomes recycling Rab5 Piccolo |
| url | https://elifesciences.org/articles/46629 |
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