Growth Arrest Specific Gene 6 Protein Concentration in Cerebrospinal Fluid Correlates with Relapse Severity in Multiple Sclerosis

Abstract

Background. Growth arrest specific gene 6 (Gas6) protein enhances survival of oligodendrocytes and neurons, and it is involved in autoimmunity. Therefore, we aimed to verify whether cerebrospinal-fluid (CSF) Gas6 concentration may represent a biomarker of disease activity in multiple sclerosis. Methods. Sixty-five patients who underwent a spinal tap during relapse of relapsing/remitting multiple sclerosis (RR-MS)(McDonald-criteria) were studied. Forty patients affected by noninflammatory/nonautoimmune neurological diseases served as controls. Relapse was defined according to Schumacher criteria. Symptoms were grouped according to Kurtzke-Functional System (FS). Clinical characteristics of the relapse, duration, Expanded-Disability-Status Scale (EDSS) change, number of FS involved, completeness of recovery, age, steroid therapy, were categorised. Patients were followed at 6-month intervals to assess relapse rate and EDSS progression. Gas6 was measured (CSF, plasma) by in-house-enzyme-linked immunoassay (ELISA). Results. Higher CSF Gas6 concentrations were observed in relapses lasting ≤60 days (8.7 ± 3.9 ng/mL) versus >60 days (6.5 ± 2.6) or controls (6.5 ± 2.4; P = 0.05), with ≤2 FS involved (8.5 ± 3.8) versus >2 FS (5.6 ± 2.5) (P < 0.05) and EDSS change ≤2.5 points (8.8 ± 3.7) versus >2.5 (6.5 ± 3.5) (P = 0.04). Conversely, CSF Gas6 was not predictive of the completeness of recovery. Plasma and CSF concentrations were not related (R 2 = 0.0003), and neither were predictive of relapse rate or EDSS progression after first relapse. Conclusions. CSF concentration of Gas6 is inversely correlated with the severity of relapse in RR-MS patients but does not predict the subsequent course of the disease.

The Gas6/TAM System and Multiple Sclerosis

“…On the other hand, CSF Gas6 concentration did not change according to the completeness of recovery. Finally, neither plasma nor CSF Gas6 were related to the relapse rate or EDSS progression in a follow up cohort [110]. These findings fit with experimental evidences, according to which Gas6 is induced during demyelination in MS murine models and probably acts with a protective role in dampening neuroinflammation and in favouring myelin repair, and are in line with the report from Weinger et al, showing that Gas6 expression was very low in chronic MS lesions [101].…”

“…Fewer, but consistent, evidence comes from human studies. However, the fact that Gas6 is scarcely expressed and sAxl and sMer decoy receptors are overexpressed in chronic MS lesions [101], and that the higher the CSF Gas6 concentration is, the milder the clinical MS relapse phenotype [110], are strong suggestions that activation of the TAM system in this setting is beneficial. The mechanisms by which Gas6 might exert this putative protection from the effects of inflammatory demyelination remain highly speculative; however, dysregulation of TAM cleavage is a hypothesis worthy of further testing.…”

Involvement of neurokinin 1 receptor within the cerebrospinal fluid-contacting nucleus in visceral pain

“…The cell bodies of these neurons are in the brain parenchyma, whereas their projections are in contact with the CSF (9,10). Previous studies have demonstrated that there are subtle changes in the chemical composition of CSF when pain occurs (11,12). Considering the specific structure of the CSF-CN, the present study hypothesized that the CSF and the CSF-CN have certain indivisible connections.…”

Gas6 Enhances Axonal Ensheathment by MBP+Membranous Processes in Human DRG/OL Promyelinating Co-Cultures

“…Gas6, detected in cerebral spinal fluid (CSF) (Sainaghi et al, 2008 , 2013 ), and expressed in neurons and stem cells, can signal through the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. In the nervous system, Gas6 is expressed and secreted by several types of neurons including motor neurons in spinal cord and large neurons of the dorsal root ganglion (DRG) (Li et al, 1996 ; Allen et al 1999 ).…”