Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase

Hadjivassiliou, Marios; Aeschlimann, Pascale; Strigun, Alexander; Sanders, David S.; Woodroofe, Nicola; Aeschlimann, Daniel

doi:10.1002/ana.21450

Cited by 235 publications

(197 citation statements)

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“…Nine distinctly expressed TGM genes are present in mammals (Fesus and Piacentini, 2002). Among them, TG 1-3 and 6 were discovered in human brain (Hadjivassiliou et al, 2008). In addition to SCA, TGs are also hypothesized to be involved in the pathogenesis of several other neurodegenerative diseases, including polyglutamine expansion diseases, Alzheimer's, Parkinson's and supranuclear palsy (Jeitner et al, 2009).…”

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confidence: 99%

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

Liu

Tang

Lan

et al. 2013

The Anatomical Record

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Our previous study identified a new form of spinocerebellar ataxia (SCA), in which mutations in the gene coding for transglutaminase 6 (TG6) were suggested to be causative. However, the data concerning cellular distribution of TG6 in the brain is still fragmentary. Therefore, we now report a comprehensive immunohistochemical examination of the expression profile of TG6 in adult mouse brain. TG6 was abundantly expressed in the septal region, basal ganglia, hypothalamus and brainstem. Notably, numerous TG6-positive neurons were found in the key brain regions involved in regulating locomotion activity, including the globus pallidus, subthalamic nucleus, substantia nigra, cerebellum, some precerebellar nuclei, and spinal motor neurons. Double immunostaining showed that the vast majority of TG6-positive neurons in the reticular nigra were GABAergic and those in the compact nigra were not dopaminergic. In addition, double staining for TG6 with either anti-NeuN or glial fibrillary acidic protein (GFAP) antibodies demonstrated exclusive NeuN-TG6 co-localization. This study presents a comprehensive overview of TG6 expression in the mouse brain, and provides insight for investigating the role of TG6 in the development of SCA. Anat Rec, 296:1576Rec, 296: -1587Rec, 296: , 2013. V C 2013 Wiley Periodicals, Inc.Key words: spinocerebellar ataxia; transglutaminase 6; immunohistochemistry; brain; distribution Abbreviations used: CNS 5 central nervous system; GABA 5 gammaaminobutyric acid; GAD67 5 glutamate acid decarboxylase 67; GFAP 5 glial fibrillary acidic protein; GFP 5 green fluorescent protein; NeuN 5 neuron specific nuclear protein; SCA 5 spinocerebellar ataxia; TGM 5 transglutaminase; TH 5 tyrosine hydroxylase.

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confidence: 99%

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

Liu

Tang

Lan

et al. 2013

The Anatomical Record

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“…Deamidation of gluten peptides enhances binding with diseaserelevant HLAs and thereby enhances presentation, leading to the development of gluten-specific CD4 + T cells resulting in inflammation leading to the typical enteropathy [15]. Whilst TG2 has been shown to be the autoantigen in CD [16] and epidermal transglutaminase TG3 has been shown to be the autoantigen in DH [17], antibodies against TG6, a primarily brain expressed transglutaminase have been shown to be present in patients with GA [10,12]. In a previous study from our group and using the same methodology, 73% of patients with gluten ataxia were positive for TG6 antibodies [10].…”

Section: Discussionmentioning

confidence: 99%

“…Determination of anti-TG6 IgA and IgG was done using in house ELISAs. The methodology has been described in detail previously [12]. Human leukocyte antigen (HLA) typing was performed by the regional blood-transfusion service.…”

Section: Standard Protocol Approvals Registrations and Patient Consmentioning

confidence: 99%

“…The discovery of TG6, a transglutaminase primarily expressed in neural tissue, has offered an opportunity for the development of a more specific marker for neurologic manifestations of gluten sensitivity as well as contributing to some clarification of the pathophysiology of neurological involvement [8,9]. Like TG2 in Coeliac Disease (CD) and TG3 in dermatitis herpetiformis, TG6 is likely to be the autoantigen in gluten related diseases where the primary manifestation is neurological [1].…”

Section: Introductionmentioning

confidence: 99%

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Transglutaminase 6 antibodies in gluten neuropathy

Zis

Rao

Sarrigiannis

et al. 2017

Digestive and Liver Disease

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“…Currently, cysteamine is already in phase I studies in humans with HD [81] , but several side effects, such as nausea, motor impairment and dosing schedule have been reported as reasons for non-adherence during phase II studies in human patients affected by cystinosis [82,83] . Another critical problem in the use of TG inhibitors in treating neurological diseases relates to the fact that, as previously reported, the human brain contains at least four TGs, including TG1, 2, 3 [22] and TG6 [84] , and a strong non-selective inhibitor of TGs might also inhibit plasma Factor XIIIa, causing a bleeding disorder. Therefore, from a number of standpoints it would seem that a selective inhibitor, which discriminates between TGs, would be preferable to an indiscriminate TG inhibitor.…”

Section: Role Of the Transglutaminases In Neurodegenerative Diseasesmentioning

confidence: 99%

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

Gatta¹,

Cammarota²,

Iannaccone³

et al. 2016

Journal of Biochemistry and Molecular Biology Research

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characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity. BIOCHEMISTRY OF THE TRANSGLUTAMINASESTransglutaminases (TGs, E.C. 2.3.2.13) are family of Ca 2+ -dependent enzymes which catalyze post-translational modifications of proteins. Examples of TG-catalyzed reactions include: (1) acyl transfer between the g-carboxamide group of a protein/polypeptide glutaminyl residue and the e-amino group of a protein/polypeptide lysyl residue; (2) attachment of a polyamine to the g-carboxamide of a glutaminyl residue; (3) deamidation of the g-carboxamide group of a protein/polypeptide glutaminyl residue (Figure 1) [1,2] . The reactions catalyzed by TGs occur by a two-step mechanism (ping-pong type), (Figure 2 ABSTRACTTransglutaminases are a family of Ca 2+ -dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono-or bi-substituted/crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological and pathological processes. In particular, transglutaminase activity has been shown to be

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Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase

Cited by 235 publications

References 51 publications

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

Transglutaminase 6 antibodies in gluten neuropathy

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

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