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

Liu, Yutao; Tang, Beisha; Lan, Wei; Song, Ning‐Ning; Huang, Ying; Zhang, Lei; Guan, Wenjuan; Shi, Yuting; Shen, Lu; Jiang, Hong; Guo, Jifeng; Xia, Kun; Ding, Yu; Wang, Junling

doi:10.1002/ar.22741

Cited by 20 publications

(12 citation statements)

References 19 publications

(26 reference statements)

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“…Our results are supported by Caputo and coworkers which observed that prolonged treatment of human intestinal Caco-2 cell line (extensively used as a model of the intestinal barrier) with p31-43 increased TG2 protein expression, indicating a non-tissue-specific post-translational mechanism of the gliadin peptide 31-43 24 . Furthermore, it has been shown that TG6 immunoreactivity is present in the CA3 region, but not in CA1/CA2 or in the dentate gyrus (DG) 25 thus supporting our in vitro results in which we observed that p31-43 exacerbates kainate neurotoxicity selectively in the CA3 region of hippocampal slices. Hence, we tested the non-selective TGs inhibitor Z-DON-Val-Pro-Leu-OMe (Z-DON) 26 as a possible neuroprotective drug in our system.…”

Section: Discussionsupporting

confidence: 92%

The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models

Gerace

Resta²,

Landucci

et al. 2017

Sci Rep

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Many neurological disorders of gluten-related diseases (GRD), not directly referable to the gastrointestinal tract, have been reported in association with celiac disease (CD), including ataxia, neuropathy and epilepsy. In particular, people with epilepsy diagnosed with CD seems to be characterized by intractable seizure. In these patients, gluten restriction diet has resulted in a reduction of both seizure frequency and antiepileptic medication. Many hypotheses have been suggested, however, molecular mechanisms that associates GRD and epileptogenesis are yet unknown. In this study, we examined the effects of the toxic gliadin peptide 31-43 in in vivo and in vitro models of kainate-induced-epilepsy. We observed that p31-43 exacerbates kainate neurotoxicity in epilepsy models, through the involvement of the enzymatic activity of transglutaminases. Moreover, electrophysiological recordings in CA3 pyramidal neurons of organotypic hippocampal slices show that p31-43 increases the inward current induced by kainate, the average sEPSC amplitude and the total number of evoked action potentials when applicated alone, thus suggesting that p31-43 is able to influence CA3-CA1 neurotransmission and can potentiate postsynaptic kainate receptors. Our results suggest a possible mechanism underlying the relationship between GRD and epilepsy through a potentiation of kainate-induced neurotoxicity and links the toxic effects of gluten to epilepsy.

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Section: Discussionsupporting

confidence: 92%

The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models

Gerace

Resta²,

Landucci

et al. 2017

Sci Rep

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“…TG6 is expressed in a subset of neurons in the cerebellar cortex (Purkinje cells) and cerebellar nuclei, but also in the thalamus. 13,14 The thalamus is involved in motor control in terms of acting as a relay center between the cerebellum and the motor cortex. 15 The observed significant thalamic atrophy and tendency toward cerebellar atrophy are therefore in line with loss or impairment of TG6þ neurons, potentially affecting GABA-ergic inhibitory pathways.…”

Section: Discussionmentioning

confidence: 99%

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6

Hadjivassiliou

Croall

Zis

et al. 2019

Clinical Gastroenterology and Hepatology

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BACKGROUND & AIMS:Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS:We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging of the brain, magnetic resonance (MR) spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction. RESULTS:Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from magnetic resonance imaging, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients-these patients had significant atrophy of subcortical brain regions compared with patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later. CONCLUSIONS:In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

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“…26 In adult mice, TG6 is primarily and abundantly expressed in neurons across the central nervous system, including spinal motor neurons, and TG6 expression is associated with neurogenesis during central nervous system development and in regions associated with motor function. 13,27 The gene encoding TG6 (TGM6; NM_198994 and NM_001254734) has recently been identified as a novel causative gene of one form of spinocerebellar ataxia. 28,29 Taken together, these findings provide increasing evidence that TG6 may play an important role in motor control and that autoantibodies to TG6 might interfere with its action and be involved in the pathogenesis of neurodegenerative diseases.…”

Section: Role Of Tg6 Autoantibodies In the Neuronal Damage In Alsmentioning

confidence: 99%

“…12 Tissue transglutaminase 6 is primarily expressed in the brain. 13 The prevalence of TG6 antibodies (IgA and/or IgG) was reported in 62% of patients with gluten ataxia and in 45% of those with CD without neurologic manifestations. 12 The TG6 antibodies are sensitive and specific in gluten ataxia.…”

mentioning

confidence: 97%

Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis

Gadoth¹,

Bleiberg²,

Klein

et al. 2015

JAMA Neurol

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IMPORTANCE Celiac disease is an autoimmune disorder triggered by gluten in genetically predisposed individuals. Gluten sensitivity can cause neurologic manifestations, such as ataxia or neuropathy, with or without gastrointestinal symptoms. Many patients with gluten ataxia produce antibodies toward the newly identified neuronal transglutaminase 6 (TG6). Two case reports described patients initially diagnosed with amyotrophic lateral sclerosis (ALS) and ultimately with celiac disease who improved with a strict gluten-free diet. OBJECTIVE To evaluate the prevalence of celiac disease-related antibodies and HLA antigen alleles, as well as TG6 antibodies, in patients with ALS and healthy individuals serving as controls to determine whether a neurologic presentation of a gluten-related disorder mimicking ALS might occur in some patients. DESIGN, SETTING, AND PARTICIPANTS In a case-control study conducted in an ALS tertiary center, we measured serum levels of total IgA antibodies, IgA antibodies to transglutaminase 2 (TG2) and endomysium, as well as IgA and IgG antibodies to deamidated gliadine peptide and TG6 and performed HLA antigen genotyping in 150 consecutive patients with ALS and 115 healthy volunteers of similar age and sex. Participants did not have any known autoimmune or gastroenterologic disorder and were not receiving any immunomodulatory medications. The study was conducted from July 1, 2010, to December 31, 2012. MAIN OUTCOMES AND MEASURES Antibody levels and frequency of individuals with abnormal antibody values as well as frequency of HLA antigen alleles were compared between patient and control groups. RESULTS All patients and control group participants were seronegative to IgA antibodies to TG2, endomysium, and deamidated gliadine peptide. Twenty-three patients (15.3%) were seropositive to TG6 IgA antibodies as opposed to only 5 controls (4.3%) (P = .004). The patients seropositive for TG6 showed a classic picture of ALS, similar to that of seronegative patients. Fifty patients and 20 controls were tested for celiac disease-specific HLA antigen alleles; 13 of 22 TG6 IgA seropositive individuals (59.1%) were seropositive for celiac disease-related alleles compared with 8 (28.6%) of the 28 seronegative individuals (P = .04). Mean (SD) levels of IgA antibodies to TG2 were 1.78 (0.73) in patients and 1.58 (0.68) in controls (normal, <10). In a subset of study participants, mean levels of deamidated gliadin peptide autoantibodies were 7.46 (6.92) in patients and 6.08 (3.90) in controls (normal, <16). Mean levels of IgA antibodies to TG6 were 29.3 (30.1) in patients and 21.0 (27.4) in controls (P = .02; normal, <26). CONCLUSIONS AND RELEVANCE The data from this study indicate that, in certain cases, an ALS syndrome might be associated with autoimmunity and gluten sensitivity. Although the data are preliminary and need replication, gluten sensitivity is potentially treatable; therefore, this diagnostic challenge should not be overlooked.

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

Cited by 20 publications

References 19 publications

The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models

The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6

Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis

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