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VPS10P-domain receptors — regulators of neuronal viability and function

Nature Reviews Neuroscience volume 9, pages 899–909 (2008)Cite this article

Key Points

  • Regulated protein transport between the cell surface and distinct intracellular compartments of the endo- and exocytic apparatus is a crucial determinant of cellular function. Proper protein trafficking is particularly relevant for highly polarized cell types, such as neurons.

  • Vacuolar protein sorting 10 protein (VPS10P)-domain receptors are sorting receptors that control the intracellular trafficking of target proteins in neurons. Their functions are crucial for pathways that regulate neuronal viability.

  • Sortilin is a VPS10P-domain receptor that interacts with pro-neurotrophins and their receptor p75NTR. Sortilin's functions are required both for controlled release of neurotrophic factors and for pathways through which neurotrophins signal the death or survival of neurons.

  • Sorting protein-related receptor with A-type repeats (SORLA) is another VPS10P-domain receptor. It prevents the transport of the amyloid precursor protein (APP) into cellular pathways for proteolytic processing to the neurotoxic peptide amyloid-β, the main constituent of senile plaques. Low expression of the receptor results in accelerated APP processing and plaque formation and represents a major risk factor for sporadic Alzheimer's disease.

Abstract

VPS10P-domain receptors, such as SORLA and sortilin, constitute a recently identified class of type-1 receptors that are expressed in neurons. Family members are multifunctional proteins that target a range of ligands, including trophic factors and neuropeptides but also other transmembrane proteins. New findings have revealed unexpected roles for VPS10P-domain receptors as regulators of neuronal viability and function through the regulation of both protein transport and signal transduction. Loss of these activities might contribute to the pathophysiology of devastating disorders of the nervous system, including Alzheimer's disease, affective disorders and post-traumatic neuronal cell death.

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Figure 1: Structural and evolutionary conservation of VPS10P-domain receptors.
Figure 2: Cellular trafficking of VPS10P-domain receptors.
Figure 3: Role of sortilin in (pro)neurotrophin action.
Figure 4: Pathways in the processing and signalling of amyloid precursor protein.
Figure 5: Role of SORLA in the trafficking and processing of amyloid precursor protein.

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Acknowledgements

We are indebted to our colleagues for critical reading of the manuscript and to M. Andrade for help with computational analysis. Work from the authors' laboratories was supported by the Deutsche Forschungsgemeinschaft (DFG), the European Commission, the Alzheimer Forschungsinitiative e.V., the Danish Medical Research Council and the Lundbeck Foundation.

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  1. MIND Centre, Department of Medical Biochemistry, University of Aarhus, Ole Worms Allé 1170, DK-8000 Aarhus C, Denmark.

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  1. Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125, Berlin, Germany

    Thomas E. Willnow, Claus M. Petersen & Anders Nykjaer

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  1. Thomas E. Willnow
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  2. Claus M. Petersen
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Correspondence to Thomas E. Willnow or Anders Nykjaer.

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Glossary

Adaptor protein

A protein that contributes to cellular function by recruiting other proteins to a complex. Such proteins often contain several protein–protein interaction domains.

Early endosome

A vesicle that contains molecules that have been internalized from the exterior of the cell through receptor-mediated endocytosis.

Retrograde sorting

Protein transport from axonal nerve endings back to the cell body (the opposite of anterograde sorting).

Secretory granule

A vesicle that stores molecules that are destined for controlled release from the cell into the medium.

Splice variant

An alternative form of a protein derived from alternative processing of its mRNA.

Amyloidogenic and non-amyloidogenic pathways

Cellular processes that promote (amyloidogenic) or interfere with (non-amyloidogenic) the deposition of plaques.

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Willnow, T., Petersen, C. & Nykjaer, A. VPS10P-domain receptors — regulators of neuronal viability and function. Nat Rev Neurosci 9, 899–909 (2008). https://doi.org/10.1038/nrn2516

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