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Review
. 2017 Jan 23;18(1):227.
doi: 10.3390/ijms18010227.

Prelysosomal Compartments in the Unconventional Secretion of Amyloidogenic Seeds

Helena Borland  1 , Frederik Vilhardt  2
Affiliations
Review

Prelysosomal Compartments in the Unconventional Secretion of Amyloidogenic Seeds

Helena Borland et al. Int J Mol Sci. .

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.

Keywords: autophagosomes; late endosomes; neurodegeneration; unconventional secretion; α-synuclein.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Entry of autophagosomes into the endolysosomal system. The closed autophagosome is contained by two membranes, which allows the ultrastructural distinction of autophagosomes from any other organelle, as the outer membrane is lost upon the first fusion reaction. The autophagosomal Soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) syntaxin17 and Atg14, which both influence later fusion reactions, are present on the phagosome Phosphatidylinositol 4-kinase (PI4K)II and its lipid product phosphatidylinositol 4-phosphate (PI4P) is specifically required for autophagososomes and late endosomes to form the hybrid organelle, an amphisome, in a fusion reaction mediated by Homotypic fusion and protein sorting (HOPS) and syntaxin17/Synaptosomal-associated protein (SNAP)29. Atg14 may primarily exert its function also at this stage. The subsequent fusion with lysosomes is also dependent on HOPS and syntaxin17/SNAP29, which partner up to form fusion competent trans-SNARE complexes with lysosomal SNARE Vesicle-associated membrane protein (VAMP)8. Alternative SNAREs for this fusion reaction are potentially v-SNARE Vesicle transport through interaction with t-SNAREs homolog 1B (Vti1b) and t-SNARE VAMP7. A number of factors have recently been identified that promote syntaxin17/SNAP29/VAMP8 interactions in different forms. ATG14 binds syntaxin17 directly, while Microtubule-associated proteins 1A/1B light chain 3B (LC3B) recruits both Pleckstrin homology domain-containing family M (PLEKHM) and Ectopic P-Granules Autophagy Protein 5 Homolog (EPG5) to the autophagosome. Here EPG5 (3) stabilizes the trans-SNARE complex with VAMP8, while PLEKHM (1) and ATG14 (2) interact with the bivalent SNARE pair syntaxin17/SNAP29.
Figure 2
Figure 2
Import of cytosolic α-synuclein into intraluminal vesicles of multivesicular bodies and late endosomes. (Right) Nfdip1 recruits the E3 ubiquitin ligase Nedd4 to the limiting membrane of multivesicular bodies and late endosomes. Neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) ubiquitinates (Ub) α-synuclein, which thereby becomes a substrate of the Endosomal sorting complex required for transport (ESCRT) machinery for import into intraluminal vesicles (ILVs; exosomes upon secretion per convention). Secreted α-synuclein is not ubitiquitinated, as ubiquitin is removed by ESCRT-IV before scission of the budding intraluminal vesicle. Alternatively (Left), aggregated and lipophilic proteins, to which amyloids conform, can enter into ILVs by a mechanism that is independent of the ESCRT machinery. The circumstances of import, and whether this form of import involves alternative ceramide- or CD63-based forms of ILV formation, remain unknown.
Figure 3
Figure 3
Mechanisms of lysosomal deficiency. (1) Normal delivery of the 50+ lysosomal acid hydrolases can become compromised by the lack of individual functional hydrolases or more generally by the derangement of Trans-Golgi network (TGN)-endosome trafficking affecting retromer (VPS35 mutations) function and its client Mannose-6-phosphate receptor (M6PR), the receptor for sorting of many hydrolases from TGN to the endosome; (2) In some lipid storage diseases SNAREs, required for entry of autophagosomes into the endolysosomal system, become “trapped” in cholesterol-enriched microdomains of lipid-laden late endosomes/lysosomes; (3) Proton and calcium fluxes are also affected in Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Presenilin (PSEN) mutations compromise sorting and/or function of the v-Adenosine Triphosphatase (ATPase) leading to relative alkalisation of the lysosome with reduced proteolysis. PSEN mutations also indirectly affect calcium efflux through mucolipin channels. The lysosomal phenotype contributed by Leucine-rich repeat kinase 2 (LRKK2) mutations can be rescued by Two-pore channel (TCP2) calcium channel knock-down; (4) ATP13A2 positively regulates ILV formation in late endosomes, and ATP13A2 mutations confer reduced luminal acidification and proteolysis that can be rescued by overexpression of synaptotagmin 11; (5) Autolysosome reformation is inhibited by gene products associated with neurological disease including clec16A, spastizin and spatacsin, and PI4K.
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