SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions
SNAP25 is one of three neuronal SNAREs driving synaptic vesicle exocytosis. We studied three mutations in SNAP25 that cause epileptic encephalopathy: V48F, and D166Y in the synaptotagmin-1 (Syt1)-binding interface, and I67N, which destabilizes the SNARE complex. All three mutations reduced Syt1-depe...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
March 1, 2024
|
| In: |
eLife
Year: 2024, Jahrgang: 12, Pages: 1-44 |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.88619 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.7554/eLife.88619
|
| Verfasserangaben: | Anna Kádková, Jacqueline Murach, Maiken Østergaard, Andrea Malsam, Jörg Malsam, Fabio Lolicato, Walter Nickel, Thomas H Söllner, Jakob Balslev Sørensen |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1896066240 | ||
| 003 | DE-627 | ||
| 005 | 20241205153839.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240723s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.7554/eLife.88619 |2 doi | |
| 035 | |a (DE-627)1896066240 | ||
| 035 | |a (DE-599)KXP1896066240 | ||
| 035 | |a (OCoLC)1475303945 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 32 |2 sdnb | ||
| 100 | 1 | |a Kádková, Anna |e VerfasserIn |0 (DE-588)1336590300 |0 (DE-627)1896073506 |4 aut | |
| 245 | 1 | 0 | |a SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions |c Anna Kádková, Jacqueline Murach, Maiken Østergaard, Andrea Malsam, Jörg Malsam, Fabio Lolicato, Walter Nickel, Thomas H Söllner, Jakob Balslev Sørensen |
| 246 | 3 | 0 | |a twentyfive |
| 264 | 1 | |c March 1, 2024 | |
| 300 | |b Illustrationen | ||
| 300 | |a 44 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Veröffentlicht: Feb 27, 2024 | ||
| 500 | |a Gesehen am 23.07.2024 | ||
| 520 | |a SNAP25 is one of three neuronal SNAREs driving synaptic vesicle exocytosis. We studied three mutations in SNAP25 that cause epileptic encephalopathy: V48F, and D166Y in the synaptotagmin-1 (Syt1)-binding interface, and I67N, which destabilizes the SNARE complex. All three mutations reduced Syt1-dependent vesicle docking to SNARE-carrying liposomes and Ca2+-stimulated membrane fusion in vitro and when expressed in mouse hippocampal neurons. The V48F and D166Y mutants (with potency D166Y > V48F) led to reduced readily releasable pool (RRP) size, due to increased spontaneous (miniature Excitatory Postsynaptic Current, mEPSC) release and decreased priming rates. These mutations lowered the energy barrier for fusion and increased the release probability, which are gain-of-function features not found in Syt1 knockout (KO) neurons; normalized mEPSC release rates were higher (potency D166Y > V48F) than in the Syt1 KO. These mutations (potency D166Y > V48F) increased spontaneous association to partner SNAREs, resulting in unregulated membrane fusion. In contrast, the I67N mutant decreased mEPSC frequency and evoked EPSC amplitudes due to an increase in the height of the energy barrier for fusion, whereas the RRP size was unaffected. This could be partly compensated by positive charges lowering the energy barrier. Overall, pathogenic mutations in SNAP25 cause complex changes in the energy landscape for priming and fusion. | ||
| 650 | 4 | |a encephalopathy | |
| 650 | 4 | |a exocytosis | |
| 650 | 4 | |a hippocampal neurons | |
| 650 | 4 | |a SNARE | |
| 650 | 4 | |a SNAREopathy | |
| 650 | 4 | |a synaptic transmission | |
| 650 | 4 | |a synaptotagmin | |
| 700 | 1 | |a Murach, Jacqueline Isabell |d 1993- |e VerfasserIn |0 (DE-588)1336481978 |0 (DE-627)1896022286 |4 aut | |
| 700 | 1 | |a Østergaard, Maiken |e VerfasserIn |4 aut | |
| 700 | 1 | |a Malsam, Andrea |d 1984- |e VerfasserIn |0 (DE-588)142096989 |0 (DE-627)704142449 |0 (DE-576)327871474 |4 aut | |
| 700 | 1 | |a Malsam, Jörg |e VerfasserIn |0 (DE-588)111982480X |0 (DE-627)872906957 |0 (DE-576)182093875 |4 aut | |
| 700 | 1 | |a Lolicato, Fabio |e VerfasserIn |0 (DE-588)1215510608 |0 (DE-627)1726683931 |4 aut | |
| 700 | 1 | |a Nickel, Walter |e VerfasserIn |0 (DE-588)1060271311 |0 (DE-627)799356964 |0 (DE-576)416359817 |4 aut | |
| 700 | 1 | |a Söllner, Thomas |e VerfasserIn |0 (DE-588)106829941X |0 (DE-627)820037842 |0 (DE-576)169500071 |4 aut | |
| 700 | 1 | |a Sørensen, Jakob Balslev |e VerfasserIn |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t eLife |d Cambridge : eLife Sciences Publications, 2012 |g 12(2024), Artikel-ID RP88619, Seite 1-44 |h Online-Ressource |w (DE-627)728518384 |w (DE-600)2687154-3 |w (DE-576)372567576 |x 2050-084X |7 nnas |a SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions |
| 773 | 1 | 8 | |g volume:12 |g year:2024 |g elocationid:RP88619 |g pages:1-44 |g extent:44 |a SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions |
| 856 | 4 | 0 | |u https://doi.org/10.7554/eLife.88619 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20240723 | ||
| 993 | |a Article | ||
| 994 | |a 2024 | ||
| 998 | |g 106829941X |a Söllner, Thomas |m 106829941X:Söllner, Thomas |d 700000 |d 711000 |e 700000PS106829941X |e 711000PS106829941X |k 0/700000/ |k 1/700000/711000/ |p 8 | ||
| 998 | |g 1060271311 |a Nickel, Walter |m 1060271311:Nickel, Walter |d 700000 |d 711000 |e 700000PN1060271311 |e 711000PN1060271311 |k 0/700000/ |k 1/700000/711000/ |p 7 | ||
| 998 | |g 1215510608 |a Lolicato, Fabio |m 1215510608:Lolicato, Fabio |d 700000 |d 711000 |e 700000PL1215510608 |e 711000PL1215510608 |k 0/700000/ |k 1/700000/711000/ |p 6 | ||
| 998 | |g 111982480X |a Malsam, Jörg |m 111982480X:Malsam, Jörg |d 700000 |d 711000 |e 700000PM111982480X |e 711000PM111982480X |k 0/700000/ |k 1/700000/711000/ |p 5 | ||
| 998 | |g 142096989 |a Malsam, Andrea |m 142096989:Malsam, Andrea |d 700000 |d 711000 |e 700000PM142096989 |e 711000PM142096989 |k 0/700000/ |k 1/700000/711000/ |p 4 | ||
| 998 | |g 1336481978 |a Murach, Jacqueline Isabell |m 1336481978:Murach, Jacqueline Isabell |d 700000 |d 711000 |e 700000PM1336481978 |e 711000PM1336481978 |k 0/700000/ |k 1/700000/711000/ |p 2 | ||
| 999 | |a KXP-PPN1896066240 |e 4555912691 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"note":["Gesehen am 28.06.17"],"language":["eng"],"recId":"728518384","physDesc":[{"extent":"Online-Ressource"}],"disp":"SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactionseLife","type":{"bibl":"periodical","media":"Online-Ressource"},"part":{"pages":"1-44","volume":"12","text":"12(2024), Artikel-ID RP88619, Seite 1-44","extent":"44","year":"2024"},"origin":[{"dateIssuedDisp":"2012-","dateIssuedKey":"2012","publisher":"eLife Sciences Publications","publisherPlace":"Cambridge"}],"id":{"zdb":["2687154-3"],"eki":["728518384"],"issn":["2050-084X"]},"titleAlt":[{"title":"eLife journal"}],"pubHistory":["1.2012 -"],"title":[{"title":"eLife","title_sort":"eLife"}]}],"id":{"eki":["1896066240"],"doi":["10.7554/eLife.88619"]},"origin":[{"dateIssuedDisp":"March 1, 2024","dateIssuedKey":"2024"}],"note":["Veröffentlicht: Feb 27, 2024","Gesehen am 23.07.2024"],"person":[{"family":"Kádková","given":"Anna","role":"aut","roleDisplay":"VerfasserIn","display":"Kádková, Anna"},{"family":"Murach","given":"Jacqueline Isabell","role":"aut","roleDisplay":"VerfasserIn","display":"Murach, Jacqueline Isabell"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Østergaard, Maiken","family":"Østergaard","given":"Maiken"},{"display":"Malsam, Andrea","roleDisplay":"VerfasserIn","role":"aut","family":"Malsam","given":"Andrea"},{"display":"Malsam, Jörg","role":"aut","roleDisplay":"VerfasserIn","family":"Malsam","given":"Jörg"},{"roleDisplay":"VerfasserIn","role":"aut","display":"Lolicato, Fabio","family":"Lolicato","given":"Fabio"},{"family":"Nickel","given":"Walter","display":"Nickel, Walter","roleDisplay":"VerfasserIn","role":"aut"},{"display":"Söllner, Thomas","role":"aut","roleDisplay":"VerfasserIn","family":"Söllner","given":"Thomas"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Sørensen, Jakob Balslev","family":"Sørensen","given":"Jakob Balslev"}],"physDesc":[{"noteIll":"Illustrationen","extent":"44 S."}],"recId":"1896066240","language":["eng"],"type":{"media":"Online-Ressource","bibl":"article-journal"},"name":{"displayForm":["Anna Kádková, Jacqueline Murach, Maiken Østergaard, Andrea Malsam, Jörg Malsam, Fabio Lolicato, Walter Nickel, Thomas H Söllner, Jakob Balslev Sørensen"]},"title":[{"title":"SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions","title_sort":"SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions"}]} | ||
| SRT | |a KADKOVAANNSNAP25DISE1202 | ||