GAS1 is present in the cerebrospinal fluid and is expressed in the choroid plexus of the adult rat

Ayala-Sarmiento, Alberto E.; Estudillo, Enrique; Pérez‐Sánchez, Gilberto; Sierra-Sánchez, Arturo; González‐Mariscal, Lorenza; Martínez‐Fong, Daniel; Segovia, José

doi:10.1007/s00418-016-1449-0

Cited by 9 publications

(7 citation statements)

References 71 publications

(114 reference statements)

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“…This is particularly important given that studies in model organisms have sometimes failed to translate to the human condition. GDE2 is the only known GPI anchor-cleaving enzyme in vertebrates that functions at the cell surface in neurons to release GPI-anchored proteins into the extracellular space (26), and GPIanchored proteins can partition to the cerebrospinal fluid (52)(53)(54). Accordingly, determining whether GPI-anchored protein release is impaired in the biofluids of patients with AD could validate the relevance of GDE2 dysfunction to AD and additionally hold promise as diagnostic biomarkers for AD.…”

Section: Discussionmentioning

confidence: 99%

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

Nakamura

Choi

et al. 2021

Sci. Transl. Med.

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A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer’s disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)–anchored inhibitor of ADAM10. In AD, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. These studies identify GDE2 control of RECK surface activity as essential for ADAM10 α-secretase function and physiological APP processing. Moreover, our results suggest the involvement of the GDE2-RECK-ADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.

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Section: Discussionmentioning

confidence: 99%

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

Nakamura

Choi

et al. 2021

Sci. Transl. Med.

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“…Interestingly, we observed two bands for Gas1 in the Western Blot analysis. We had previously reported that there are two isoforms of Gas1 (one of 37 kDa and the other ≈ 34 kDa) [ 49 ]. Perhaps the second band found in the glomerulus is another Gas1 isoform weighing <37 kDa previously described.…”

Section: Discussionmentioning

confidence: 99%

“…This is a very relevant observation since the proximal convoluted tubule is the region of the nephron that performs almost all the reabsorption and secretion of the main solutes in the kidney [ 52 ]. And since there is evidence indicating that Gas1 is secreted by podocytes and/or mesangial cells in the adult [ 12 ] and by perivascular cells in the liver [ 49 ], we believe that more work is necessary in the future to determine the specific cell populations of the nephron that express Gas1 and can also secrete it. We hypothesize that Gas1 may participate in local signaling (autocrine and/or endocrine), as well as paracrine communication and perhaps at as of yet scarcely explored systemic level, since a wide distribution of the soluble form of Gas1 has been found in the body fluids of the rat (cerebrospinal fluid (CSF), blood plasma [ 49 ] and urine [ 12 ]).…”

Section: Discussionmentioning

confidence: 99%

“…And since there is evidence indicating that Gas1 is secreted by podocytes and/or mesangial cells in the adult [ 12 ] and by perivascular cells in the liver [ 49 ], we believe that more work is necessary in the future to determine the specific cell populations of the nephron that express Gas1 and can also secrete it. We hypothesize that Gas1 may participate in local signaling (autocrine and/or endocrine), as well as paracrine communication and perhaps at as of yet scarcely explored systemic level, since a wide distribution of the soluble form of Gas1 has been found in the body fluids of the rat (cerebrospinal fluid (CSF), blood plasma [ 49 ] and urine [ 12 ]). Interestingly, in a previous report, no significant difference was found between the levels of soluble Gas1 present in blood plasma and CSF [ 49 ], reflecting the important role that the kidney may play in regulating the concentration of Gas1 in order to maintain isotonic concentration.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesize that Gas1 may participate in local signaling (autocrine and/or endocrine), as well as paracrine communication and perhaps at as of yet scarcely explored systemic level, since a wide distribution of the soluble form of Gas1 has been found in the body fluids of the rat (cerebrospinal fluid (CSF), blood plasma [ 49 ] and urine [ 12 ]). Interestingly, in a previous report, no significant difference was found between the levels of soluble Gas1 present in blood plasma and CSF [ 49 ], reflecting the important role that the kidney may play in regulating the concentration of Gas1 in order to maintain isotonic concentration.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the pattern of expression of Gas1 in the kidney during postnatal development in the rat

et al. 2023

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Growth Arrest-Specific 1 (Gas1) is a pleiotropic protein with different functions, in the adult kidney Gas1 acts as an endogenous inhibitor of cell proliferation but it is also necessary for the maintenance and proliferation of Renal Progenitor Cells (RPC) during early development, thus it fulfills important functions in the adult kidney. However, it is not known whether or not Gas1 is expressed during postnatal development, a critical stage for renal maturation. For this reason, the main objective of this work was to characterize the expression pattern of Gas1 in the different regions of the kidney by immunofluorescence and Western blot analysis during the postnatal development of the rat. We found that Gas1 is present and has a differential expression pattern in the various regions of the nephron during postnatal development. We observed that the highest levels of expression of Gas1 occur in the adult, however, Gas1 is also expressed in RPC and interestingly, the expression of RPC markers such as the Neural cell adhesion molecule (NCAM) and Cluster of differentiation 24 (CD24) were found to have an inverse pattern of expression to Gas1 (decreases as the kidney matures) during postnatal renal maturation, this indicates a role for Gas1 in the regulation of renal cell proliferation at this stage of development.

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Expression of Gas1 in Mouse Brain: Release and Role in Neuronal Differentiation

et al. 2017

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Growth arrest-specific 1 (Gas1) is a pleiotropic protein that induces apoptosis of tumor cells and has important roles during development. Recently, the presence of two forms of Gas1 was reported: one attached to the cell membrane by a GPI anchor; and a soluble extracellular form shed by cells. Previously, we showed that Gas1 is expressed in different areas of the adult mouse CNS. Here, we report the levels of Gas1 mRNA protein in different regions and analyzed its expressions in glutamatergic, GABAergic, and dopaminergic neurons. We found that Gas1 is expressed in GABAergic and glutamatergic neurons in the Purkinje-molecular layer of the cerebellum, hippocampus, thalamus, and fastigial nucleus, as well as in dopaminergic neurons of the substantia nigra. In all cases, Gas1 was found in the cell bodies, but not in the neuropil. The Purkinje and the molecular layers show the highest levels of Gas1, whereas the granule cell layer has low levels. Moreover, we detected the expression and release of Gas1 from primary cultures of Purkinje cells and from hippocampal neurons as well as from neuronal cell lines, but not from cerebellar granular cells. In addition, using SH-SY5Y cells differentiated with retinoic acid as a neuronal model, we found that extracellular Gas1 promotes neurite outgrowth, increases the levels of tyrosine hydroxylase, and stimulates the inhibition of GSK3β. These findings demonstrate that Gas1 is expressed and released by neurons and promotes differentiation, suggesting an important role for Gas1 in cellular signaling in the CNS.

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GAS1 is present in the cerebrospinal fluid and is expressed in the choroid plexus of the adult rat

Cited by 9 publications

References 71 publications

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

Characterization of the pattern of expression of Gas1 in the kidney during postnatal development in the rat

Expression of Gas1 in Mouse Brain: Release and Role in Neuronal Differentiation

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