Plasma ubiquitin-proteasome system profile in patients with multiple sclerosis: correlation with clinical features, neuroimaging, and treatment with interferon-beta-1b.

OBJECTIVE

Interferon-beta-1b (IFN-beta-1b) reduces relapses in multiple sclerosis (MS) and improves magnetic resonance imaging (MRI) outcomes. Mechanism of action of IFN-beta-1b is only marginally understood. The roles and plasma levels of factors within the ubiquitin-proteasome system (UPS) and the plasma proteasome enzymatic activity of MS patients have not been explored. We hypothesized that pharmacologic double inhibition of the UPS by IFN-beta-1b occurs in MS patients and contributes to improvement of clinical course and reduction in MRI activity.

METHODS

During a 6-month prospective study, we measured plasma proteasome and ubiquitin protein levels and the proteasome enzymatic activities in patients with MS pre- (n = 35) and post-treatment (n = 26) with IFN-beta-1b and 96 normal controls. The results were compared to clinical and brain MRI outcomes.

RESULTS

Plasma levels of ubiquitin and proteasome enzymatic activities were elevated in MS patients before therapy with IFN-beta-1b as compared to normals (P < 0.01). Additionally, UPS enzymatic activities were increased in MS patients before treatment with IFN-beta-1b (P < 0.0001). Six months after treatment with IFN-beta-1b, plasma levels of proteasome and ubiquitin showed further elevation as compared to the pre-treatment values and normals. Treatment with IFN-beta-1b suppressed the enzymatic activity of plasma proteasome and such lowered level of enzymatic activity correlated with a decline in the number of post-contrast T1-weighted enhancing lesions.

CONCLUSION

Since UPS is linked to protein degradation, it may contribute to the course of immune-mediated diseases such as MS, and pharmacologic inhibition of UPS through IFN-beta-1b therapy improves the clinical course of MS. Larger clinical trials are needed to confirm the results of this preliminary study.