Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases

Eder, Ursula; Leitner, Bernd; Kirchmair, Rudolf; Pohl, Peter; Ka, Jobst; Smith, A.D.; Málly, Judit; Benzer, A.; Riederer, Peter; Reichmann, Heinz; Saria, Alois; Winkler, Hans

doi:10.1007/s007020050036

Cited by 36 publications

(19 citation statements)

References 33 publications

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“…Inflammatory microglia are characteristic of many neurological diseases, and the identification of the responsible agents may therefore be relevant for novel therapeutic strategies. Increased levels of CGA in cerebrospinal fluids have been found in patients with Parkinson's disease (55) and has been correlated with early synaptic degeneration in Alzheimer's disease (56). Our findings point to the possibility that CGA accumulation is an early marker for the diagnosis of brain inflammation and that CGAinduced neurotoxicity may be limited by the use of anti-inflammatory drugs.…”

Section: Discussionsupporting

confidence: 51%

Mechanisms Underlying Neuronal Death Induced by Chromogranin A-activated Microglia

Ciesielski-Treska¹,

Ulrich²,

Chasserot‐Golaz³

et al. 2001

Journal of Biological Chemistry

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The neurotoxic effects of activated microglia in neurodegenerative diseases are well established. We recently provided evidence that chromogranin A (CGA), a multifunctional protein localized in dystrophic neurites and in senile plaques, induces an activated phenotype and secretion of neurotoxins by rat microglia in culture. In the present study, we focused on the mechanisms underlying neuronal degeneration triggered by CGAactivated microglia. We found that neuronal death exhibits apoptotic features, characterized by the externalization of phosphatidylserine and the fragmentation of DNA. Microglial neurotoxins markedly stimulate the phosphorylation and activity of neuronal p38 mitogenactivated protein kinase and provoke the release of mitochondrial cytochrome c, which precedes apoptosis. Inhibition of p38 kinase with SB 203580 partially protects neurons from death induced by CGA-activated microglia. Furthermore, neurons are also protected by Fas-Fc, which antagonizes the interactions between the death receptor Fas and its ligand FasL and by cell-permeable peptides that inhibit caspases 8 and 3. Thus, CGA triggers the release of microglial neurotoxins that mobilize several death-signaling pathways in neurons. Our results further support the idea that CGA, which is upregulated in many neuropathologies, represents a potent endogeneous inflammatory factor possibly responsible for neuronal degeneration.

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Section: Discussionsupporting

confidence: 51%

Mechanisms Underlying Neuronal Death Induced by Chromogranin A-activated Microglia

Ciesielski-Treska¹,

Ulrich²,

Chasserot‐Golaz³

et al. 2001

Journal of Biological Chemistry

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“…These data suggest that its major physiological role in this system is not to act as a precursor for bioactive peptides. Although Holthuis and coauthors (36) have reported proteolytic fragments that derive from SgIII, no biological activity has been assigned to any of the resulting peptides, in contrast with the situation for the CgA and CgB (37)(38)(39). It remains to be seen whether any SgIIIderived fragments act as signaling peptides in neuroendocrine cells, and we have not seen any evidence that pharmacological or immunological activation of mast cells can induce proteolysis of SgIII.…”

Section: Discussioncontrasting

confidence: 60%

Secretogranin III Directs Secretory Vesicle Biogenesis in Mast Cells in a Manner Dependent upon Interaction with Chromogranin A

Prasad

Yanagihara

Small‐Howard

et al. 2008

The Journal of Immunology

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Mast cells are granular immunocytes that reside in the body’s barrier tissues. These cells orchestrate inflammatory responses. Proinflammatory mediators are stored in granular structures within the mast cell cytosol. Control of mast cell granule exocytosis is a major therapeutic goal for allergic and inflammatory diseases. However, the proteins that control granule biogenesis and abundance in mast cells have not been elucidated. In neuroendocrine cells, whose dense core granules are strikingly similar to mast cell granules, granin proteins regulate granulogenesis. Our studies suggest that the Secretogranin III (SgIII) protein is involved in secretory granule biogenesis in mast cells. SgIII is abundant in mast cells, and is organized into vesicular structures. Our results show that over-expression of SgIII in mast cells is sufficient to cause an expansion of a granular compartment in these cells. These novel granules store inflammatory mediators that are released in response to physiological stimuli, indicating that they function as bona fide secretory vesicles. In mast cells, as in neuroendocrine cells, we show that SgIII is complexed with Chromogranin A (CgA). CgA is granulogenic when complexed with SgIII. Our data show that a novel non-granulogenic truncation mutant of SgIII (1–210) lacks the ability to interact with CgA. Thus, in mast cells, a CgA-SgIII complex may play a key role in secretory granule biogenesis. SgIII function in mast cells is unlikely to be limited to its partnership with CgA, as our interaction trap analysis suggests that SgIII has multiple binding partners, including the mast cell ion channel TRPA1.

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“…Reduced levels of CGB were found in distinct subregions of the hippocampus from individuals with schizophrenia (39). In contrast, increased levels of CGB were found in the cerebrospinal fluid, Lewy bodies, and axonal swellings of patients with Parkinson's disease (25,40,41). A combination of increased and decreased CGB expression levels was found throughout the hippocampus of individuals with Alzheimer's disease where a layer-specific distribution of CGB was present (30,42).…”

Section: Discussionmentioning

confidence: 83%

Functional Coupling of Chromogranin with the Inositol 1,4,5-Trisphosphate Receptor Shapes Calcium Signaling

Choe

Harrison

Grant

et al. 2004

Journal of Biological Chemistry

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Chromogranins A and B are high capacity, low affinity calcium (Ca 2؉ ) storage proteins that bind to the inositol 1,4,5-trisphosphate-gated receptor (InsP 3 R). Although most commonly associated with secretory granules of neuroendocrine cells, chromogranins have also been found in the lumen of the endoplasmic reticulum (ER) of many cell types. To investigate the functional consequences of the interaction between the InsP 3 R and the chromogranins, we disrupted the interaction between the two proteins by adding a chromogranin fragment, which competed with chromogranin for its binding site on the InsP 3 R. Responses were monitored at the single channel level and in intact cells. When using InsP 3 R type I incorporated into planar lipid bilayers and activated by cytoplasmic InsP 3 and luminal chromogranin, the addition of the fragment reversed the enhancing effect of chromogranin. Moreover, the expression of the fragment in the ER of neuronally differentiated PC12 cells attenuated agonist-induced intracellular Ca 2؉ signaling. These results show that the InsP 3 R/chromogranin interaction amplifies Ca 2؉ release from the ER and that chromogranin is an essential component of this intracellular channel complex. Ca2ϩ functions as a second messenger in excitable and nonexcitable cells, playing an important role in development, gene transcription, synaptic modulation, and secretion (1, 2). The cytosolic Ca 2ϩ concentration can be increased by entry of extracellular Ca 2ϩ via voltage-operated, receptor-operated, or store-operated Ca 2ϩ channels (3). In addition, Ca 2ϩ release from intracellular stores by ryanodine receptors and inositol 1,4,5-trisphosphate receptors (InsP 3 R) 1 plays a pivotal role in the modulation of intracellular Ca 2ϩ signals (1, 4 -6). The InsP 3 R type 1, which is predominantly found in the cerebellum, plays an important role in neuronal functions such as long term potentiation and depression (7) and has recently been implicated in the etiology of neurological diseases such as Huntington's disease (8). The InsP 3 R is regulated by phosphorylation (9), ubiquitation (10), and association with luminal and cytosolic proteins (11,12). Among the proteins associating with the InsP 3 R, only the high capacity, low affinity Ca 2ϩ storage proteins, chromogranins A and B (CGA and CGB), have been shown to bind to the InsP 3 R on the luminal side (13,14). CGA and CGB are members of the granin family and can be found in a wide variety of endocrine and neuroendocrine cells as well as in neurons of the peripheral and central nervous systems (15,16).CGA and CGB have numerous extracellular and intracellular functions. One extracellular function is that chromogranins act as hormones after being proteolytically processed into peptides such as pancreastatin (17, 18), vasostatins I and II (19 -21), parastatin (22), catestatin (23), and chromacin (24). Elevated levels of circulating chromogranins were found in patients with endocrine and neuroendocrine tumors, renal failure, and heart failure. Chromogranins and their met...

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Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases

Cited by 36 publications

References 33 publications

Mechanisms Underlying Neuronal Death Induced by Chromogranin A-activated Microglia

Mechanisms Underlying Neuronal Death Induced by Chromogranin A-activated Microglia

Secretogranin III Directs Secretory Vesicle Biogenesis in Mast Cells in a Manner Dependent upon Interaction with Chromogranin A

Functional Coupling of Chromogranin with the Inositol 1,4,5-Trisphosphate Receptor Shapes Calcium Signaling

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