Jaiswal JK, Fix M, Takano T, Nedergaard M, Simon SM.
Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes.
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14151-6.
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Two interesting new papers have just been published reporting that astrocytes contain secretory lysosomes. Lysosomes are membrane-bound organelles that are found in all mammalian cells and contain hydrolases and lipases required for protein and membrane degradation. In many cells of the immune system, however, lysosomes also contain secretory proteins that can be released by regulated exocytosis in response to an external stimulus, providing different cell types with a wide range of effector functions (see http://scienceweek.com/2004/sa041119-1.htm). Secretory lysosomes are still poorly understood but have been linked to a wide range of possible functions, including the secretion of cytokines like interleukin-1 that lack a classical secretory signal sequence, exosome secretion, control of membrane lipid composition, and membrane repair (1). Using optical imaging to study calcium-triggered secretion from astrocytes, Jaiswal et al. (2) in this study show that lysosomes undergo calcium-dependent exocytosis in astrocytes. Zhang et al. (3) show that lysosomes in astrocytes contain abundant ATP. By imaging FM dye-labeled puncta, together with total internal reflection fluorescence microscopy, these authors show that this lysosomal ATP is released in response to calcium-dependent stimuli, such as glutamate application. These stimuli induce calcium waves that propagate through the astrocyte syncytium and induce release of ATP onto nearby synapses, blood vessels, or other astrocytes. Interestingly, secretory lysosomes in oligodendrocytes have also recently been shown to play a critical role in triggering PLP and myelin membrane exocytosis to form myelin (4).
These new findings raise many questions. First, in the CNS, is this lysosomal compartment unique to glial cells, or do neurons also share a similar exocytosis pathway? Gene profiling studies suggest that many of the lysosomal components thought to be highly expressed within this pathway, such as CD63, NPC1/2, and ABCA1, are highly enriched in astrocytes and oligodendrocytes, but hardly expressed by mature mouse forebrain neurons (5). Thus it is possible that neurons and glial cells have specialized secretory pathways for their unique functions.
But what would the function of secretory lysosomes be in astrocytes? One role, as shown by Zhang et al. (3), is that they may mediate regulated release of ATP by astrocytes. Astrocytes also highly express high levels of certain proteins such as FGF1 that lack a classical secretory sequence. Thus it is an interesting possibility that this pathway participates in release of these proteins. Another important role of secretory lysosomes is in regulating the lipid composition of the cell membrane. Therefore, an important question raised by these new results is whether secretory lysosomes play a role in cholesterol homeostasis in the brain, or perhaps in ApoE release or composition. Even more speculatively, because amyloid filaments bind avidly to ApoE lipoprotein particles, might amyloid formation or buildup occur initially in secretory lysosomes?
Together, these new findings provide an exciting new insight into the function of astrocytes and raise many new questions for future studies.
References:1. Stinchcombe J, Bossi G, Griffiths GM. Linking albinism and immunity: the secrets of secretory lysosomes.
Science. 2004 Jul 2;305(5680):55-9. Review.
2. Jaiswal J, Fix M, Takano T, Nedergaard M, Simon S (2007) Resolving vesicle fusion from lysis to monitor calcium triggered lysosomal exocytosis in astrocytes. PNAS, in press
3. Zhang Z, Chen G, Zhou W, Song A, Xu T, Luo Q, Wang W, Gu XS, Duan S. Regulated ATP release from astrocytes through lysosome exocytosis.
Nat Cell Biol. 2007 Aug;9(8):945-53. Epub 2007 Jul 8.
4. Trajkovic K, Dhaunchak AS, Goncalves JT, Wenzel D, Schneider A, Bunt G, Nave KA, Simons M. Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites.
J Cell Biol. 2006 Mar 13;172(6):937-48. Epub 2006 Mar 6.
5. Cahoy J, Emery B, Kaushal A, Foo L, Zamanian J, Christopherson K, Xing Y, Lubishcher J, Krieg P, Krupenko S, Thompson W, Barres B (2007) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. Submitted.