%0 Journal Article
%T Current Understanding on the Role of Standard and Immunoproteasomes in Inflammatory/Immunological Pathways of Multiple Sclerosis
%A Elena Bellavista
%A Aurelia Santoro
%A Daniela Galimberti
%A Cristoforo Comi
%A Fabio Luciani
%A Michele Mishto
%J Autoimmune Diseases
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/739705
%X The ubiquitin-proteasome system is the major intracellular molecular machinery for protein degradation and maintenance of protein homeostasis in most human cells. As ubiquitin-proteasome system plays a critical role in the regulation of the immune system, it might also influence the development and progression of multiple sclerosis (MS). Both ex vivo analyses and animal models suggest that activity and composition of ubiquitin-proteasome system are altered in MS. Proteasome isoforms endowed of immunosubunits may affect the functionality of different cell types such as CD8+ and CD4+ T cells and B cells as well as neurons during MS development. Furthermore, the study of proteasome-related biomarkers, such as proteasome antibodies and circulating proteasomes, may represent a field of interest in MS. Proteasome inhibitors are already used as treatment for cancer and the recent development of inhibitors selective for immunoproteasome subunits may soon represent novel therapeutic approaches to the different forms of MS. In this review we describe the current knowledge on the potential role of proteasomes in MS and discuss the pro et contra of possible therapies for MS targeting proteasome isoforms. 1. Multiple Sclerosis and Proteasome Isoforms Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by the presence of inflammation, myelin damage, and axonal degeneration. There are two main clinical courses of multiple sclerosis: about 90% of MS patients experience the relapsing-remitting MS phase (RRMS), characterized by disability episodes followed by a complete or partial recovery. Multifocal lesions are found by magnetic resonance imaging, typically but not exclusively, in the white matter of the optic nerve, brain stem, cerebellum, and spinal cord. Some lesions are enhanced after intravenous administration of gadolinium, indicating breakdown of the blood-brain barrier (BBB) as a result of active inflammation. The majority of RRMS patients enter into a secondary progressive phase (SPMS), characterized by a variable degree of inflammation and a continuous and progressive neurological decline in disability state (with or without superimposed relapses) [1, 2]. A minor percentage (10%) of MS patients shows a primary progressive form of MS (PPMS), characterized by progression of neurological disability from onset. Clinically relevant factors differentiating RRMS and PPMS are age at disease onset (a decade later in PPMS) and gender (1£¿:£¿1.3 male/female in PPMS versus 1£¿:£¿2 in RRMS) [3]. Although the initial course of RRMS
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