Get started
Work

Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling

Year: 2026
Type: preprint
Abstract: Efficient transport of membrane proteins through the endosomal network is essential for brain development and function, with perturbation implicated in disease. Deficiencies in Retromer, a key regulator of endosomal transport, have been linked to aging-related neurodegenerative disorders including Alzheimer’s and Parkinson’s disease. To better define the neuroprotective role of Retromer, we have applied cell surface restricted proteomics to identify those integral membrane proteins whose recycling to the plasma membrane is mediated by Retromer and associated cargo adaptors, sorting nexin 3 (SNX3), its paralogue sorting nexin 12 (SNX12), and sorting nexin 27 (SNX27) (data available via ProteomeXchange: PXD078277). By comparing primary rat cortical neurons and astrocytes we have identified several cargoes that require either SNX3/SNX12- or SNX27-Retromer complexes for endosomal recycling, including proteins involved in synapse organisation, synaptic signalling and Alzheimer’s disease pathology. We highlight that perturbed Retromer function leads to endosomal enlargement, and we establish a key role of SNX27-Retromer in modulating transport of glutamate across both neuronal and astrocytic membranes via recycling of glutamate transporters EAAT3 (SLC1A1) and EAAT1 (SLC1A3) respectively. Our study provides further mechanistic insight into the consequences of Retromer deficiency for neuronal and astrocytic function, offering new avenues of research in the treatment of neurodegenerative disease. Abstract Figure Graphical Abstract Suppression of Retromer and the sorting nexins (SNX27, SNX3/SNX12) leads to a significant change in the surface proteome of rat cortical neurons and astrocytes. Focusing on the glutamate transporters, SLC1A1 and SLC1A3, we have validated that SNX27-Retromer is required for their trafficking, with SNX27-Retromer suppression in astrocytes leading to a loss of glutamate uptake.
DOI: 10.64898/2026.05.14.724903
Authors: Emma Jones, Helena Adams, Kai-en Chen, Fabeeha Maroof, Therese M. Ibbotson, Yasuko Nakamura, Paul J. Banks, Michael D. Healy, Philip A. Lewis, Kate J. Heesom, Brett M. Collins, Kevin A. Wilkinson, Peter J. Cullen, Kirsty J. McMillan
Language: English
Subfield: Cell Biology
Open Access status: green
Funders: Wellcome Trust, Royal Society, Academy of Medical Sciences, Lister Institute of Preventive Medicine, Medical Research Council, Australian Research Council, National Health and Medical Research Council
Awards: G1057686810, From structural mechanisms of endosomal trafficking to therapies for neurodegenerative diseases, Structure of the essential Commander protein trafficking complex, Towards a thorough mechanistic understanding of endosomal cargo sorting., G5051481983, G5692665522, Endosomal retrieval sub-domain organisation, dynamics and function in human health and disease, Defining the role of retromer-like in endolysosomal cargo sorting in health and disease., Towards a thorough mechanistic understanding of endosomal cargo sorting., Analysing the cell biology of SNX10 in endosomal sorting and signaling: implications for osteoclast function in osteopetrosis, G787455810
OpenAlex ID: W7161593354
Cites:
Cited by:
Related to: 10