The P56S mutation in VAPB (vesicle-associated membrane protein-associated protein B) causes autosomal dominant motoneuronal diseases. Although it was reported that the P56S mutation induces localization shift of VAPB from endoplasmic reticulum (ER) to non-ER compartments, it remains unclear what the physiological function of VAPB is and how the P56S mutation in VAPB causes motoneuronal diseases. Here we demonstrate that overexpression of wild type VAPB (wt-VAPB) promotes unfolded protein response (UPR), which is an ER reaction to suppress accumulation of misfolded proteins, and that small interfering RNA for VAPB attenuates UPR to chemically induced ER stresses, indicating that VAPB is physiologically involved in UPR. The P56S mutation nullifies the function of VAPB to mediate UPR by inhibiting folding of VAPB that results in insolubility and aggregate formation of VAPB in non-ER fractions. Furthermore, we have found that expression of P56S-VAPB inhibits UPR, mediated by endogenous wt-VAPB, by inducing aggregate formation and mislocalization into non-ER fractions of wt-VAPB. Consequently, the P56S mutation in a single allele of the VAPB gene may diminish the activity of VAPB to mediate UPR to less than half the normal level. We thus speculate that the malfunction of VAPB to mediate UPR, caused by the P56S mutation, may contribute to the development of motoneuronal degeneration linked to VAPB/ALS8.
The role of tumor necrosis factor a (TNF-a) in the pathogenesis of autoimmune diabetes mellitus was tested in the nonobese mouse (NOD) model system. The effects of TNF-a were assessed on three levels: (i) insulitis development, (ii) development of overt diabetes, (iii) adoptive transfer of diabetes by splenic lymphocytes. Spontaneous diabetes mellitus was blocked in NOD mice by long-term treatment with recombinant TNF-a. Treatment with TNF-a caused'a significant reduction in the lymphocytic infiltration associated with the destruction of the insulin-producing beta cells. Class II major histocompatibility complex Ia expression by islet cells was not up-regulated by TNF-a. Moreover, TNF-a was able to suppress the induction of diabetes in adoptive transfer of lymphocytes from diabetic female mice to young nondiabetic male NOD mice. These activities of TNF-a were shared by interleukin la in this system. These studies have implications for the pathogenesis and therapy of autoimmune diabetes mellitus.Nonobese diabetic (NOD) mice spontaneously develop diabetes remarkably similar to human autoimmune insulindependent diabetes mellitus. There is increasing evidence that the human and the NOD disease result from immune destruction of the insulin-producing beta cells in the islets of Langerhans (1). The disease is characterized by progressive lymphocyte infiltration into the islets (insulitis) prior to the expression of overt diabetes and by the appearance of anti-islet cell antibodies in the serum (2). A T-cell-mediated autoimmune pathogenesis is implicated because the disease can be passively transferred with lymphocytes into irradiated prediabetic mice (3) and prevented by treatment with antibodies directed against Thy-1.2 (4) and L3T4 (5) or by treatment with cyclosporin A (6). Diabetes can also be prevented by treatment with antibodies to class II Ia antigens (7). Untreated animals develop profound glucose intolerance and ketosis and die within weeks of the onset of overt diabetes. The role of lymphokines, especially interferon y (IFN-y), interleukin 1 (IL-1), and tumor necrosis factor a (TNF-a), in the pathogenesis of autoimmune diabetes has received increasing attention recently (8, 9). It was shown that IFN--y and TNF-a can induce the aberrant expression of class II major histocompatibility complex (MHC) molecules on pancreatic beta cells in vitro, suggesting a role for these lymphokines in the induction of the autoimmune process in diabetes (9). A different group of investigators has suggested that IL-1 is toxic to pancreatic beta cells in vitro and that TNF-a significantly enhances this toxicity (8). Recently we have suggested that TNF-a may play a significant role in preventing autoimmune nephritis in the (NZB3 x NZW)F1 lupus nephritis model system (10). Here we present evidence that TNF-a has a major effect in vivo by protecting NOD mice from developing autoimmune insulitis and diabetes.
MATERIALS AND METHODSRecombinant murine TNF-a (0.53 mg/ml; 2.6 x 107 units/ml) was kindly provided by Genentech. Recom...
Excitotoxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). More recently, glial involvement has been shown to be essential for ALS-related motoneuronal death. Here, we identified an N-methyl-D-aspartate (NMDA) receptor co-agonist, D-serine (D-Ser), as a glia-derived enhancer of glutamate (Glu) toxicity to ALS motoneurons. Cell death assay indicated that primary spinal cord neurons from ALS mice were more vulnerable to NMDA toxicity than those from control mice, in a D-Ser-dependent manner. Levels of D-Ser and its producing enzyme, serine racemase, in spinal cords of ALS mice were progressively elevated, dominantly in glia, with disease progression. In vitro, expression of serine racemase was induced not only by an extracellular pro-inflammatory factor, but also by transiently expressed G93A-superoxide dismutase1 in microglial cells. Furthermore, increases of D-Ser levels were also observed in spinal cords of both familial and sporadic ALS patients. Collectively, Glu toxicity enhanced by D-Ser overproduced in glia is proposed as a novel mechanism underlying ALS motoneuronal death, and this mechanism may be regarded as a potential therapeutic target for ALS.
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