Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health

James L. Daly (), Chris M. Danson, Philip A. Lewis, Lu Zhao, Sara Riccardo, Lucio Filippo, Davide Cacchiarelli, Daehoon Lee, Stephen J. Cross, Kate J. Heesom, Wen-Cheng Xiong, Andrea Ballabio, James R. Edgar and Peter J. Cullen ()
Additional contact information
James L. Daly: University Walk, University of Bristol
Chris M. Danson: University Walk, University of Bristol
Philip A. Lewis: University of Bristol
Lu Zhao: Case Western Reserve University
Sara Riccardo: Armenise/Harvard Laboratory of Integrative Genomics
Lucio Filippo: Armenise/Harvard Laboratory of Integrative Genomics
Davide Cacchiarelli: Armenise/Harvard Laboratory of Integrative Genomics
Daehoon Lee: Case Western Reserve University
Stephen J. Cross: University of Bristol
Kate J. Heesom: University of Bristol
Wen-Cheng Xiong: Case Western Reserve University
Andrea Ballabio: Armenise/Harvard Laboratory of Integrative Genomics
James R. Edgar: Cambridge University, Tennis Court Road
Peter J. Cullen: University Walk, University of Bristol

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson’s and Alzheimer’s diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform an integrated multi-omics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify widespread changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide a holistic view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.

Date: 2023
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DOI: 10.1038/s41467-023-38719-8

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