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.

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background. Ann Neurol 2000;47:374–377

We evaluated the efficacy and safety of rituximab in an open-label, uncontrolled study of 13 patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (MAG) and correlated the response to therapy with clinical and laboratory features. One year after rituximab therapy, anti-MAG immunoglobulin M (IgM) titers were significantly reduced. At that time, eight patients (62%) had improved in both the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore and the Medical Research Council sumscore for muscle strength and seven of them also in the INCAT disability score. The improvement in the mean INCAT sensory sumscore was significant at 12 months and correlated with lower anti-MAG antibody at entry and at follow-up. This study suggests that rituximab may be efficacious in patients with anti-MAG associated neuropathy and particularly on sensory impairment and in those with moderately elevated antibody titers. These findings suggest that antibody reduction below a critical level may be necessary to achieve clinical improvement.

Stem cells are currently seen as a treatment for tissue regeneration in neurological diseases such as multiple sclerosis, anticipating that they integrate and differentiate into neural cells. Mesenchymal stem cells (MSCs), a subset of adult progenitor cells, differentiate into cells of the mesodermal lineage but also, under certain experimental circumstances, into cells of the neuronal and glial lineage. Their clinical development, however, has been significantly boosted by the demonstration that MSCs display significant therapeutic plasticity mainly occurring through bystander mechanisms. These features have been exploited in the effective treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis where the inhibition of the autoimmune response resulted in a significant amelioration of disease and decrease of demyelination, immune infiltrates and axonal loss. Surprisingly, these effects do not require MSCs to engraft in the central nervous system but depend on the cells' ability to inhibit pathogenic immune responses both in the periphery and inside the central nervous system and to release neuroprotective and pro-oligodendrogenic molecules favoring tissue repair. These results paved the road for the utilization of MSCs for the treatment of multiple sclerosis.

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Administration of mesenchymal stem cells (MSC) ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), at both clinical and neuropathological levels. The therapeutic properties of MSC in EAE are mainly mediated by the modulation of pathogenic immune response, but other neurotropic effects, including decreased demyelination and axonal loss as well as promotion of tissue repair, play also a role. Properly controlled phase II clinical trials to explore the potential of MSC transplantation as a treatment for MS are underway. Interferon beta (IFNβ) is an approved treatment for relapsing-remitting and secondary progressive MS. Here, we explored the possibility that IFNβ might influence the therapeutic potential of MSC, in view of possible synergistic effects as add-on therapy. IFNβ enhanced the immunomodulatory functions of MSC and induced the expression of secretory leukocyte protease inhibitor (Slpi) and hepatocyte growth factor (Hgf), two soluble mediators involved in immune and regenerative functions of MSC. At molecular level, IFNβ induced a rapid and transient phosphorylation of STAT1 and STAT3, the transcription factors responsible for Slpi and Hgf induction. Concomitantly, IFNβ dynamically affected the activity of mTOR, a key checkpoint in the control of metabolic pathways. Indeed, the impairment of mTOR activity observed early upon exposure to IFNβ, was followed by a long-lasting induction of mTOR signaling, that was associated with an increased glycolytic capacity in MSC. When induced to switch their energetic metabolism towards glycolysis, MSC showed an improved ability to control T-cell proliferation. These results suggest that modifications of MSC energetic metabolism induced by IFNβ may contribute to promote MSC immunomodulatory function and support a role for metabolic pathways in the therapeutic function of MSC. Altogether, these findings support the idea of a combined treatment for MS, in which the immunomodulatory and possibly regenerative activity of MSC could be enhanced by the administration of IFNβ.