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Int. J. Mol. Sci. 2017, 18(1), 227; doi:10.3390/ijms18010227

Prelysosomal Compartments in the Unconventional Secretion of Amyloidogenic Seeds

1
Department of Neurodegeneration In Vitro, H. Lundbeck A/S, 2500 Valby, Denmark
2
Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, 2200N Copenhagen, Denmark
*
Author to whom correspondence should be addressed.
Academic Editors: Gian-Pietro Di Sansebastiano and Antonio Gaballo
Received: 29 November 2016 / Revised: 9 January 2017 / Accepted: 16 January 2017 / Published: 23 January 2017
(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)
View Full-Text   |   Download PDF [1712 KB, uploaded 23 January 2017]   |  

Abstract

A mechanistic link between neuron-to-neuron transmission of secreted amyloid and propagation of protein malconformation cytopathology and disease has recently been uncovered in animal models. An enormous interest in the unconventional secretion of amyloids from neurons has followed. Amphisomes and late endosomes are the penultimate maturation products of the autophagosomal and endosomal pathways, respectively, and normally fuse with lysosomes for degradation. However, under conditions of perturbed membrane trafficking and/or lysosomal deficiency, prelysosomal compartments may instead fuse with the plasma membrane to release any contained amyloid. After a brief introduction to the endosomal and autophagosomal pathways, we discuss the evidence for autophagosomal secretion (exophagy) of amyloids, with a comparative emphasis on Aβ1–42 and α-synuclein, as luminal and cytosolic amyloids, respectively. The ESCRT-mediated import of cytosolic amyloid into late endosomal exosomes, a known vehicle of transmission of macromolecules between cells, is also reviewed. Finally, mechanisms of lysosomal dysfunction, deficiency, and exocytosis are exemplified in the context of genetically identified risk factors, mainly for Parkinson’s disease. Exocytosis of prelysosomal or lysosomal organelles is a last resort for clearance of cytotoxic material and alleviates cytopathy. However, they also represent a vehicle for the concentration, posttranslational modification, and secretion of amyloid seeds. View Full-Text
Keywords: autophagosomes; α-synuclein; late endosomes; unconventional secretion; neurodegeneration autophagosomes; α-synuclein; late endosomes; unconventional secretion; neurodegeneration
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Borland, H.; Vilhardt, F. Prelysosomal Compartments in the Unconventional Secretion of Amyloidogenic Seeds. Int. J. Mol. Sci. 2017, 18, 227.

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