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Retromer Binds the FANSHY Sorting Motif in SorLA to Regulate Amyloid Precursor Protein Sorting and Processing

Fjorback, Anja W., Seaman, Matthew, Gustafsen, Camilla, Mehmedbasic, Arnela, Gokool, Suzanne, Wu, Chengbiao, Militz, Daniel, Schmidt, Vanessa, Madsen, Peder, Nyengaard, Jens R., Willnow, Thomas E., Christensen, Erik Ilsø, Mobley, William B., Nykjær, Anders, Andersen, Olav M.·2012·The Journal of Neuroscience
DOI 10.1523/jneurosci.2272-11.2012
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Abstract

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.

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Crossref · 10.1523/jneurosci.2272-11.2012

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  • Newly synthesized SorLA molecules follow the constitutive secretory pathway from the ER to the cell surface through the Golgi, and undergo post-translational modifications and maturation, resulting in immature and mature species.

    “Newly synthesized SorLA molecules follow the constitutive secretory pathway from the endoplasmic reticulum (ER) to the cell surface, through the Golgi. During their transport through the secretory pathway, SorLA proteins are subjected to several post-translational modifications, including both N- and O-glycosylation, and maturation processes [3–9], resulting in the presence of immature and mature”

    From Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease (2021) · cites this paper as [6]

    The Discussion describes SorLA moving through the secretory pathway to the cell surface. The section ‘Reduced expression of sorLA-FANSHY36A at the cell surface’ reports maturation through acquisition of glycosylation, and the Figure 4 legend labels immature and mature species. Our copy does not specify both N- and O-glycosylation or explicitly trace the initial route from the ER through the Golgi. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • SORL1 encodes SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates.

    “The SORL1 gene encodes the sortilin‐related receptor protein SORLA, a sorting receptor that regulates endo‐lysosomal trafficking of various substrates.”

    From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Fjorback et al. 2012

    The Introduction identifies SORL1 as the gene encoding sorLA and describes sorLA as a sorting receptor that binds and regulates APP trafficking. The Discussion describes its endosome-to-Golgi transport, but our copy does not establish that sorLA regulates trafficking of various substrates; its substantive findings concern APP. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • SORLA is a component of the retromer endosomal trafficking complex and has been observed to bind VSP26 and SNX27 subunits of the retromer complex within the C-terminal tail domain.

    “SORLA is a component of the retromer endosomal trafficking complex and has been observed to bind VSP26 (Fjorback, Seaman et al. 2012) and SNX27 (Huang, Zhao et al. 2016) subunits of the retromer complex within the C-terminal tail domain.”

    From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Fjorback, Seaman et al. 2012

  • SORLA interacts with the retromer complex and shuttles proteins between the TGN, endosomes, and the cell surface.

    “It interacts with the multi‐protein assembly retromer and shuttles proteins between TGN, endosomes, and the cell surface (Fjorback et al. 2012; Jacobsen et al. 2001, 1996; Willnow and Andersen 2013; Yamazaki et al. 1996).”

    From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Fjorback et al. 2012

  • SORLA binds to retromer.

    “SORLA binds to retromer (Fjorback et al. 2012), which regulates the retrograde transport of the cation‐independent mannose‐6‐phosphate receptor (CIMPR) through the mannose‐6‐phosphate‐dependent pathway (M6P) (Arighi et al. 2004; Cui et al. 2019).”

    From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Fjorback et al. 2012

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Citations

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Metadata

Authors
Fjorback, A. W., Seaman, M., Gustafsen, C., Mehmedbasic, A., Gokool, S., Wu, C., Militz, D., Schmidt, V., Madsen, P., Nyengaard, J. R., Willnow, T. E., Christensen, E. I., Mobley, W. B., Nykjær, A., & Andersen, O. M.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2012-01-25
Volume
32
Issue
4
Pages
1467-1480
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.2272-11.2012
Cited by
253
References
6
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)

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