期刊
ELIFE
卷 10, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.59432
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资金
- Medical Research Council [MR/L007363/1, MR/P018807/1]
- Wellcome Trust [104568/Z/14/2, 220260/Z/20/Z]
- Lister Institute of Preventive Medicine
- National Health and Medical Research Council [APP1136021, APP1099114]
- Biotechnology and Biological Sciences Research Council [BB/R00787X/1]
- Royal Society [RSRP\R1\211004]
- Wellcome Trust [220260/Z/20/Z] Funding Source: Wellcome Trust
- BBSRC [BB/R00787X/1] Funding Source: UKRI
- MRC [MR/L007363/1, MR/P018807/1] Funding Source: UKRI
SNX27 is associated with various neuropathologies by sorting integral proteins to the synaptic surface, particularly AMPA receptors. Through regulating the endosomal sorting of LRFN2, SNX27 indirectly controls AMPA receptor-mediated synaptic transmission and plasticity, shedding light on their perturbed functions in neurological conditions.
The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies, we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities, and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions.
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