In situ enzymatic activity of transglutaminase isoforms on brain tissue sections of rodents: A new approach to monitor differences in post-translational protein modifications during neurodegeneration

Schulze-Krebs, Anja; Canneva, Fabio; Schnepf, Rebecca; Dobner, Julia; Dieterich, Walburga; Hörsten, Stephan von

doi:10.1016/j.brainres.2015.11.027

Cited by 3 publications

(9 citation statements)

References 45 publications

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“…Here, the expression of the TG6 protein was highest in the cortex, especially in the piriform cortex, the lateral septum, the olfactory tubercle and the shell of the nucleus accumbens (Figure 2A; right panel). TG6 expression was specifically localized to neurons, but not to astrocytes or microglia, as we previously confirmed using the NeuN-, Iba1-and GFAP-specific antibodies [45]. Furthermore, the reaction products of TGs, the N-ε-(γ-glutamyl)-lysine isopeptide bonds (GGEL) (Dab-Ni, black staining), could also be found in neurons next to astrocytes (Figure 2B), which appeared in close proximity to TG6 (DAB, brown staining) positive neurons (Figure 2B; arrowheads).…”

Section: Regional Colocalization Of Tg6 and The Tg-enzymatic Reaction Products In The Brain Of Tghd Ratssupporting

confidence: 79%

“…Similar results as shown in the cerebral cortex of mice, were also obtained in the olfactory tubercle of old tgHD rats (data not shown). As expected, TG1-, TG2-and TG3-specific reactivity was mostly localized on blood vessels and meninges and no age-or genotype-specific differences were detected in the animal models investigated (Supplementary Figure S1) [45].…”

Section: Tg6 Enzymatic Activity Is Prominent In Bachd Micesupporting

confidence: 77%

“…To assess specific TG6 enzymatic activity in situ, we adapted a protocol described by Esposito and colleagues for intestinal tissue [44,45]. As presented in Figure 1B (NC), no or negligible background reactivity was detectable in the absence of CaCl 2 .…”

Section: Tg6 Enzymatic Activity Is Prominent In Bachd Micementioning

confidence: 99%

“…The regional distribution of TG6 was also investigated in a second rodent model of Huntington disease, using an antibody whose specificity we recently confirmed [45]. Homozygous tgHD rats expressing a truncated 1962 bp Htt fragment with 51 repeats of the polyglutamine stretch under the control of the endogenous Htt rat promoter [42] were analyzed in comparison to wt littermates.…”

Section: Regional Colocalization Of Tg6 and The Tg-enzymatic Reaction Products In The Brain Of Tghd Ratsmentioning

confidence: 99%

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Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models

Schulze-Krebs

Canneva

Stemick

et al. 2021

IJMS

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Mammalian transglutaminases (TGs) catalyze calcium-dependent irreversible posttranslational modifications of proteins and their enzymatic activities contribute to the pathogenesis of several human neurodegenerative diseases. Although different transglutaminases are found in many different tissues, the TG6 isoform is mostly expressed in the CNS. The present study was embarked on/undertaken to investigate expression, distribution and activity of transglutaminases in Huntington disease transgenic rodent models, with a focus on analyzing the involvement of TG6 in the age- and genotype-specific pathological features relating to disease progression in HD transgenic mice and a tgHD transgenic rat model using biochemical, histological and functional assays. Our results demonstrate the physical interaction between TG6 and (mutant) huntingtin by co-immunoprecipitation analysis and the contribution of its enzymatic activity for the total aggregate load in SH-SY5Y cells. In addition, we identify that TG6 expression and activity are especially abundant in the olfactory tubercle and piriform cortex, the regions displaying the highest amount of mHTT aggregates in transgenic rodent models of HD. Furthermore, mHTT aggregates were colocalized within TG6-positive cells. These findings point towards a role of TG6 in disease pathogenesis via mHTT aggregate formation.

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Section: Regional Colocalization Of Tg6 and The Tg-enzymatic Reaction Products In The Brain Of Tghd Ratssupporting

confidence: 79%

Section: Tg6 Enzymatic Activity Is Prominent In Bachd Micesupporting

confidence: 77%

Section: Tg6 Enzymatic Activity Is Prominent In Bachd Micementioning

confidence: 99%

Section: Regional Colocalization Of Tg6 and The Tg-enzymatic Reaction Products In The Brain Of Tghd Ratsmentioning

confidence: 99%

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Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models

Schulze-Krebs

Canneva

Stemick

et al. 2021

IJMS

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“…TGs catalyze protein covalent cross-linking through transamination reactions, in which intra-or inter-molecular isopeptide bonds are formed between a glutamine residue and, usually, a lysine residue (Folk and Chung, 1973). TG6 is abundantly expressed in the brain, especially in the septal region, basal ganglia, and cerebellum Schulze-Krebs et al, 2016). Some TGs have been related to neurodegenerative diseases (AbdAlla et al, 2009;Andringa et al, 2004;Zainelli et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

TGM6 variants in Parkinson’s disease: clinical findings and functional evidence

Chen

Peng

et al. 2020

J. Integr. Neurosci.

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TGM6 encodes transglutaminase 6, which catalyzes the covalent crosslinking of proteins through transamination reactions. Variants in TGM6 have been identified as the cause of spinocerebellar ataxia type 35. However, we found 12 TGM6 variants of low frequency among 308 patients with Parkinson’s disease using next-generation sequencing technologies and multiple ligation-dependent probe amplification, including two variants TGM6 p.R111C and p.L517W, which have been reported to affect functions of transglutaminase 6 in spinocerebellar ataxia type 35 cases. The characteristics of these TGM6 carriers were summarized. To clarify the role of TGM6 variants in Parkinson’s disease, we constructed the plasmids of wild-type TGM6 and TGM6 p.R111C, p.359L, p.L517W to transfect A53T-SH-SY5Y cells and conducted transglutaminase assay, western blots, immunofluorescence, and cell viability assay. Results revealed that the distribution and expression levels of transglutaminase 6 were not affected by TGM6 variants. However, the variants showed lower transglutaminase activity than wild-type transglutaminase 6. The overexpression of wild-type TGM6 was proved to relieve the cell damage, down-regulate the level of α-synuclein and enhance autophagy. These effects were weakened in cells transfected with mutant TGM6 plasmids. Our results suggested that there may be some relationship between TGM6 and Parkinson’s disease. TGM6 carriers in Parkinson’s disease patients presented with typical parkinsonism but progressed slower. The high expression level of wild-type transglutaminase 6 may protect cells by decreasing α-synuclein and enhancing autophagy.

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Striatal Mutant Huntingtin Protein Levels Decline with Age in Homozygous Huntington’s Disease Knock-In Mouse Models

Franich

Basso

André

et al. 2018

JHD

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Background Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with aging, caused by an expanded polyglutamine (polyQ) repeat within the Huntingtin (HTT) protein. In HD, degeneration of the striatum and atrophy of the cortex are observed while cerebellum is less affected. Objective To test the hypothesis that HTT protein levels decline with age, which together with HTT mutation could influence disease progression. Methods Using whole brain cell lysates, a unique method of SDS-PAGE and western analysis was used to quantitate HTT protein, which resolves as a monomer and as a high molecular weight species that is modulated by the presence of transglutaminase 2. HTT levels were measured in striatum, cortex and cerebellum in congenic homozygous Q140 and HdhQ150 knock-in mice and WT littermate controls. Results Mutant HTT in both homozygous knock-in HD mouse models and WT HTT in control striatal and cortical tissues significantly declined in a progressive manner over time. Levels of mutant HTT in HD cerebellum remained high during aging. Conclusions A general decline in mutant HTT levels in striatum and cortex is observed that may contribute to disease progression in homozygous knock-in HD mouse models through reduction of HTT function. In cerebellum, sustained levels of mutant HTT with aging may be protective to this tissue which is less overtly affected in HD.

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In situ enzymatic activity of transglutaminase isoforms on brain tissue sections of rodents: A new approach to monitor differences in post-translational protein modifications during neurodegeneration

Cited by 3 publications

References 45 publications

Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models

Transglutaminase 6 Is Colocalized and Interacts with Mutant Huntingtin in Huntington Disease Rodent Animal Models

TGM6 variants in Parkinson’s disease: clinical findings and functional evidence

Striatal Mutant Huntingtin Protein Levels Decline with Age in Homozygous Huntington’s Disease Knock-In Mouse Models

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