Abstract
Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation and immune cell infiltration in the brain parenchyma. Tissue transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been shown to be present in infiltrating MHC-II positive cells in lesions of patients suffering from MS. Moreover, TG2 mRNA levels in peripheral blood mononuclear cells (PBMC)-derived from primary progressive (PP)-MS patients correlated with clinical parameters, thus highlighting the importance of TG2 in MS pathology. In the present study, we further characterized TG2 expression by measuring the mRNA levels of full-length TG2 and four TG2 alternative splice variants in PBMCs derived from PP-MS patients and healthy control (HC) subjects. In PP-MS-derived PBMCs, TG2 variant V4b was significantly higher expressed, and both V4a and V4b variants were relatively more expressed in relation to full-length TG2. These observations open new avenues to unravel the importance of TG2 alternative splicing in the pathophysiology of PP-MS.
Highlights
Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disorder of the central nervous system (CNS)
The expression levels of these variants are found to be altered in several diseases [10,13] which might indicate that under pathological conditions, their role could be due, diseases [10,13] which might indicate that under pathological conditions, their role could be due, at at least partly, to a relative low intracellular Ca2+2+ concentration needed for their activation
In primary progressive (PP)-MS, least partly, to a relative low intracellular Ca concentration needed for their activation
Summary
Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disorder of the central nervous system (CNS). The loss of amino acids at the C-terminus reduces GTP binding to the enzyme, thereby allowing the short variants to escape the GTP regulation This results in TGase activity when there is a transient increase in Ca2+ levels [9]. The V2 variant (TGM2_v2, 62 kDa) was observed to be increased in post-mortem brain tissue of Alzheimer’s disease patients suggesting a role in Alzheimer’s disease pathology [10]. To further characterize TG2 expression in PP-MS patients, in this study we investigated the expression profile of full-length TG2 and TG2 splice variants in PBMCs of PP-MS patients compared to those of HC subjects. This may give insight in the possible contribution of TG2 isoforms to MS pathophysiology, and in particular to that of PP-MS patients
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