Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations.

Mutations in the gene MPZ, encoding myelin protein zero (MPZ), cause inherited neuropathies collectively called Charcot-Marie-Tooth type 1B (CMT1B). Based on the age of onset, clinical and pathological features, most MPZ mutations are separable into two groups: one causing a severe, early-onset, demyelinating neuropathy and a second, causing a late-onset neuropathy with prominent axonal loss. To investigate potential pathomechanisms underlying the two phenotypes, we transiently transfected HeLa cells with two late-onset (T95M, H10P) and two early-onset (H52R, S22_W28 deletion) mutations and analyzed their effects on intracellular protein trafficking, glycosylation, cell viability and intercellular adhesion. We found that the two late-onset mutations were both transported to the cell membrane and moderately reduced MPZ-mediated intercellular adhesion. The two early-onset mutations caused two distinct abnormalities. H52R was correctly glycosylated and trafficked to the plasma membrane, but strongly affected intercellular adhesion. When co-expressed with wild-type MPZ (wtMPZ), a functional dominant negative effect was observed. Alternatively, S22_W28 deletion was retained within the cytoplasm and reduced both adhesion caused by wtMPZ and cellular viability. Since the same trafficking patterns were observed in transfected murine Schwann cells, they are not an artifact of heterologous cell expression. Our results suggest that at least some late-onset mutations cause a partial loss of function in the transfected cells, whereas multiple abnormal gain of function pathways can result in early-onset neuropathy. Further characterization of these pathways will lead to a better understanding of the pathogenesis of CMT1B and a rational basis for treating these debilitating inherited neuropathies.

The effects of a new soluble dietary fiber on weight gain and selected blood parameters in rats.

This study was designed to investigate a new dietary fiber, alpha-cyclodextrin, marketed under the trade name FBCx (Wacker Biochem, Adrian, MI), for beneficial effects on weight reduction and the improvement of certain blood parameters in rats. Male Wistar rats were divided into 4 groups and fed ad libitum for a period of 6 weeks: (1) a normal low-fat diet (LF; 4% fat wt/wt); (2) an LF diet with FBCx added; (3) a high-fat diet (HF, 40% fat wt/wt); and (4) an HF diet with FBCx. The FBCx was added at the rate of 10% (wt/wt) of the fat in the diet. Body weight and food intake were recorded 3 times per week. Plasma constituent levels and liver and fecal lipid contents, as well as body composition were determined at sacrifice. Adding FBCx to the diet significantly reduced weight gain in rats fed with an HF diet relative to rats fed with the HF control diet (P < .05). FBCx also elicited a reduction in plasma triglyceride levels of 30%, total cholesterol of 9%, and increased the fat content of the feces in the rats fed with the HF diet with FBCx. In addition, the serum leptin levels were normalized, and the calculated insulin sensitivity was improved. No adverse effects were observed in the rats consuming FBCx. It would appear that FBCx might be effective in reducing body weight gain and improving metabolic syndrome.