Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis

Abstract

ObjectiveThe clinical course of multiple sclerosis (MS) is variable and largely unpredictable pointing to an urgent need for markers to monitor disease activity and progression. Recent evidence revealed that tissue transglutaminase (TG2) is altered in patient-derived monocytes. We hypothesize that blood cell–derived TG2 messenger RNA (mRNA) can potentially be used as biomarker in patients with MS.MethodsIn peripheral blood mononuclear cells (PBMCs) from 151 healthy controls and 161 patients with MS, TG2 mRNA was measured and correlated with clinical and MRI parameters of disease activity (annualized relapse rate, gadolinium-enhanced lesions, and T2 lesion volume) and disease progression (Expanded Disability Status Scale [EDSS], normalized brain volume, and hypointense T1 lesion volume).ResultsPBMC-derived TG2 mRNA levels were significantly associated with disease progression, i.e., worsening of the EDSS over 2 years of follow-up, normalized brain volume, and normalized gray and white matter volume in the total MS patient group at baseline. Of these, in patients with relapsing-remitting MS, TG2 expression was significantly associated with worsening of the EDSS scores over 2 years of follow-up. In the patients with primary progressive (PP) MS, TG2 mRNA levels were significantly associated with EDSS, normalized brain volume, and normalized gray and white matter volume at baseline. In addition, TG2 mRNA associated with T1 hypointense lesion volume in the patients with PP MS at baseline.ConclusionPBMC-derived TG2 mRNA levels hold promise as biomarker for disease progression in patients with MS.Classification of EvidenceThis study provides Class II evidence that in patients with MS, PBMC-derived TG2 mRNA levels are associated with disease progression.

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

“…TG2 is increased in MS patient-derived monocytes, affecting their adhesion and migration into the CNS [176]. In keeping with this, elevated TG2 mRNA levels have been reported in peripheral blood mononuclear cells in MS patients, a finding that correlated with disease progression [176,177], suggesting TG2 as both a biomarker and therapeutic target for MS.…”

“…Multiple sclerosis (MS) is a relapsing-remitting or primary progressive disease characterized by neuroinflammation, demyelination, and, eventually, axon loss and neurodegeneration in the CNS. Accumulating evidence from studies has identified the involvement of TG2 in postmortem MS brain samples and in the central nervous system of the animal model for experimental autoimmune encephalomyelitis (EAE), illustrating its role in the pathogenesis of MS [174][175][176][177][178]. For example, TG2 knock-out mice subjected to the EAE model exhibited decreased disease severity compared to wild-type littermates, and treatment with the TG2 inhibitor cysteamine in the EAE effector phase in wild-type mice showed benefits [179].…”

Comparative Profiling of TG2 and Its Effectors in Human Relapsing Remitting and Progressive Multiple Sclerosis

“…TG2 possesses a wide variety of activities, from acting as a GTPase and kinase to a transamidase and scaffolding protein with many substrates across various intracellular compartments, the cell surface, and within the extracellular space. These interactions are important for cell survival [ 27 , 28 ] and the phagocytic function of the macrophages in tissue repair [ 29 , 30 , 31 ], but can also contribute to increased inflammation [ 32 ] and cell-death [ 33 ] in neurodegenerative conditions [ 34 ], including Huntington disease (HD) [ 35 ], Alzheimer disease (AD) [ 36 ], Amyotrophic Lateral Sclerosis (ALS) [ 37 ], and Multiple Sclerosis (MS) [ 38 , 39 , 40 , 41 ]. Recently, our group and others identified TG2 dysregulation in cadaveric MS brain samples and in the CNS of rodents with EAE (experimental autoimmune encephalomyelitis) [ 38 ], highlighting its role in the pathogenesis of MS.…”

“…In EAE, TG2 is expressed in infiltrating monocytes [ 41 ], promoting their adhesion and tissue migration into the CNS [ 41 ]. Sestito et al [ 39 ] demonstrated that this elevated TG2 in the monocytes of MS patients correlated with the progression of the clinical course of disease in MS [ 39 , 42 ], suggesting that TG2 is an important therapeutic target to alter the disease course in MS. Extracellular TG2 also crosslinks with various extracellular matrix (ECM) molecules such as Fibronectin (FN) [ 43 ] and Heparin Sulfate Proteoglycan (HSPG) [ 44 ], which are known to mediate inflammation and promote tissue scarring, which is inhibitory to repair [ 45 ]. Selective deletion of TG2 in astrocytes has been demonstrated to perturb the production of the chondroitin sulfate proteoglycan (CSPG) NG2 after spinal cord injury (SCI) [ 46 ] and to improve neuronal survival when these TG2 depleted astrocytes are co-cultured with neurons in vitro following exposure to cytotoxic stimuli [ 47 ].…”