Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior
Background The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteri...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2024
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| Online Access: | https://hdl.handle.net/1721.1/155667 |
| _version_ | 1824458141914365952 |
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| author | Ahumada-Marchant, Constanza Ancatén-Gonzalez, Carlos Haensgen, Henny Brauer, Bastian Merino-Veliz, Nicolas Droste, Rita Arancibia, Felipe Horvitz, H. Robert Constantine-Paton, Martha Arriagada, Gloria Chávez, Andrés E. Bustos, Fernando J. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ahumada-Marchant, Constanza Ancatén-Gonzalez, Carlos Haensgen, Henny Brauer, Bastian Merino-Veliz, Nicolas Droste, Rita Arancibia, Felipe Horvitz, H. Robert Constantine-Paton, Martha Arriagada, Gloria Chávez, Andrés E. Bustos, Fernando J. |
| author_sort | Ahumada-Marchant, Constanza |
| collection | MIT |
| description | Background
The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown.
Results
To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments.
Conclusions
We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions. |
| first_indexed | 2024-09-23T12:18:17Z |
| format | Article |
| id | mit-1721.1/155667 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2025-02-19T04:21:11Z |
| publishDate | 2024 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1556672025-01-09T04:49:28Z Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior Ahumada-Marchant, Constanza Ancatén-Gonzalez, Carlos Haensgen, Henny Brauer, Bastian Merino-Veliz, Nicolas Droste, Rita Arancibia, Felipe Horvitz, H. Robert Constantine-Paton, Martha Arriagada, Gloria Chávez, Andrés E. Bustos, Fernando J. Massachusetts Institute of Technology. Department of Biology Howard Hughes Medical Institute McGovern Institute for Brain Research at MIT Background The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. Results To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. Conclusions We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions. 2024-07-12T15:37:54Z 2024-07-12T15:37:54Z 2024-06-26 2024-06-30T03:11:18Z Article http://purl.org/eprint/type/JournalArticle 1741-7007 https://hdl.handle.net/1721.1/155667 Ahumada-Marchant, C., Ancatén-Gonzalez, C., Haensgen, H. et al. Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior. BMC Biol 22, 142 (2024). PUBLISHER_CC en 10.1186/s12915-024-01940-y BMC Biology Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ The Author(s) application/pdf Springer Science and Business Media LLC BioMed Central |
| spellingShingle | Ahumada-Marchant, Constanza Ancatén-Gonzalez, Carlos Haensgen, Henny Brauer, Bastian Merino-Veliz, Nicolas Droste, Rita Arancibia, Felipe Horvitz, H. Robert Constantine-Paton, Martha Arriagada, Gloria Chávez, Andrés E. Bustos, Fernando J. Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior |
| title | Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior |
| title_full | Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior |
| title_fullStr | Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior |
| title_full_unstemmed | Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior |
| title_short | Deletion of VPS50 protein in mouse brain impairs synaptic function and behavior |
| title_sort | deletion of vps50 protein in mouse brain impairs synaptic function and behavior |
| url | https://hdl.handle.net/1721.1/155667 |
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