Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex.

Autor:	Morris K; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom., Bulovaite E; Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Kaizuka T; Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Schnorrenberg S; EMBL Imaging Centre, European Molecular Biology Laboratory, Heidelberg, Germany., Adams CT; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom.; IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom., Komiyama N; Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.; Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.; The Patrick Wild Centre for Research into Autism, Fragile X Syndrome & Intellectual Disabilities, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Mendive-Tapia L; IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.; Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Grant SGN; Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.; Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom., Horrocks MH; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom.; IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Nov 21; Vol. 13. Date of Electronic Publication: 2024 Nov 21.
DOI:	10.7554/eLife.99303
Abstrakt:	The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick's 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick's model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored. Competing Interests: KM, EB, TK, SS, CA, NK, LM, SG, MH No competing interests declared (© 2024, Morris et al.)
Databáze:	MEDLINE
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