Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.In the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.Taken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE

The role of sphingolipids in the control of skeletal muscle function: a review.

In this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue

IDENTIFICATION OF A SKELETAL-MUSCLE TRANSVERSE TUBULAR H+ PUMP

Characterization study of transverse tubule Mg-ATPas

IDENTIFICATION OF COMMON STRUCTURAL DOMAINS BETWEEN THE SR CA-ATPASE AND THE TT MG-ATPASE

Identification of structural homologies between the sarcoplasmic reticulum Ca-ATPase and the transverse tubule Mg-ATPas

Sphyngomyelin derivatives influence the trophism of skeletal muscles.

Large evidence demonstrates that sphingomyelin derivatives exert important extracellular actions. Among these lipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), present at high levels in plasma, exert their action by stimulating specific receptors expressed in almost all tissues. As a result, S1P and SPC are able to control important cell functions, such as growth, migration, proliferation and survival. Recent evidence, produced in our laboratory, suggests that these two lipids are trophic factors of skeletal muscle. Skeletal muscle fibres express at least three of the five specific S1P/SPC receptors. One of these receptors, S1P1, is localized at cell membrane and its expression level and localization vary depending on diverse conditions, such as fibre type, animal age, loss of innervations, and during regeneration. Importantly, we have recently demonstrated that S1P sustains contractile activity of skeletal muscle, particularly during fatigue. Finally, we have also evidenced the presence of a rheostat mechanism at muscle fibre surface competent to convert a potentially adverse lipid, sphingosine (SPH), into a positive compound, S1P, an action operated by the enzyme SPH kinase. Based on these results, we advanced the hypothesis that S1P and SPC could be trophic factors of skeletal muscle and their action regulated by contractile activity. As a consequence, the regulatory action of sphingomyelin derivatives is probably compromised under disuse conditions, particularly in the microgravity environment. To establish the trophic function of S1P and SPC (but also of SPH, being the precursor of S1P), we have utilized a typical experimental model of disuse, muscle denervation, by employing two opposite approaches: the denervated muscle was either treated with extra doses of the lipids or the level of circulating S1P was reduced. The results show that the increased level of both SPH, SPC and S1P, delivered at constant rate to the muscle through mini-osmotic pumps, determined a significant reduction of the expected atrophy produced by the absence of the nerve. Among the three lipids, SPC was the most successful by producing early and substantial trophic effects, while SPH was efficacious in slowing the typical slow-to-fast transformation of denervated muscle. The lipids also affected the expression of myogenic factors, suggesting they could regulate the processing of satellite cells. On the other hand, the marked reduction of circulating S1P, obtained by treating the denervated animal with an antibody specific for the lipid, caused a dramatic increase of the atrophy of the denervated muscle. These results thus identify sphingomyelin derivatives as trophic factors of skeletal muscle and, as a consequence, suggest that the regulation of their plasma level could represent a suitable intervention to attenuate, if not prevent, the progressive muscle atrophy generated by space flight as well as in diverse muscle disuse condition

Inability of Sphingosine and Calmodulin to Control Ryanodine Receptor in Malignant Hyperthermia

Sarcoplasmic reticulum Ca 2+ release of malignant hyperthermia-susceptible (MHS) skeletal muscle is hypersensitive to both agonists and antagonists of the ryanodine receptor channel. This study examined whether sphingosine and calmodulin, endogenous modulators of the channel, play a role in the abnormal responsiveness of pathological muscle. Sphingosine caused a dose dependent inhibition of [ 3 H]ryanodine binding to MHS and normal terminal cisterns (TC) membranes of the sarcoplasmic reticulum (SR). The sphingosine concentration capable of inhibiting 50 % of the binding (IC 50) was 1.5-times higher for MHS compared to membranes isolated form normal animals. Calmodulin also caused a dose dependent inhibition of [ 3 H]ryanodine binding. However, at variance with sphingosine and other inhibitors, the calmodulin effect was incomplete in that 1 µM calmodulin inhibited only 50 % of the [ 3 H]ryanodine binding to MHS membranes. Sphingosine’s inhibitory action was particularly effective at activating pCa levels (5 to 4) in normal membranes, while in MHS membranes the ability of sphingosine to block ryanodine receptor was minimal. Similarly, Calmodulin inhibition of [ 3 H]ryanodine binding was maximal in normal membranes at pCa 4 but less potent in MHS membranes. Both sphingosine and calmodulin exert the highest inhibitory action to the ryanodine receptor at activating pCa levels in normal membranes. Similarly, at the same pCa values, both drugs are less effective in blocking the mutated channel. i.e., particularly at pCa levels that maximally activate muscle cells. These results indicate that the lower sensitivity to inhibition of the MHS Ca 2+-release channel by endogenous antagonists, such as sphingosine and calmodulin, may play an important role in the abnormal response of the mutated channel