Targeting transglutaminase 2 as a potential disease modifying therapeutic strategy for synucleinopathies

Zhang, Jie; Jasutkar, Hilary Grosso; Mouradian, M. Maral

doi:10.4103/1673-5374.303027

Cited by 3 publications

(5 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, C277S mutation is also deficient in the GDP/GTP binding ability of TG2 [28], thus limiting the utility of this mutant for examining the specific role of TG2 transamidation activity in numerous biological processes. To this end, mutating W241 in the enzymatic core to an alanine (W241A) specifically abolishes the crosslinking enzymatic activity of TG2 while preserving its GTPase function [29] and provides a preferred genetic tool to study specifically its transamidation activity in vitro and in vivo [27,30]. TG2 is well characterized regarding its Ca 2+ -dependent crosslinking and transamidation activities, which allow it to modify substrate proteins post translationally via the formation of covalent bonds [31].…”

Section: Structure and Multifunctional Activities Of Tg2mentioning

confidence: 99%

“…Accumulating evidence has shown that α-Syn is a target of TG2 transamidation activity in vitro and in vivo [30,[143][144][145][146], implicating TG2 activity in α-Syn aggregation and the pathogenesis of synucleinopathies (Figure 2g). In a neuroblastoma SH-SY5Y cellular model, increased TG2 activity and TG2-dependent α-Syn crosslinking were detected following exposure to the dopaminergic toxin 1-methyl-4-phenylpyridine (MPP (+)), while the pharmacological blockade of TG2 with Z006 was found to inhibit this effect [147].…”

Section: Tg2 In Parkinson's Disease and Dementia With Lewy Bodiesmentioning

confidence: 99%

“…Notably, in vivo studies in genetically modified mice that are transgenic for α-Syn and either over-express TG2 (TG2 Tg /Syn Tg ) or have deletion of the TG2 gene (TG2 −/− /Syn Tg ) support the contribution of TG2 to the pathogenesis of PD by crosslinking α-Syn [30,145,146]. Specifically, high-molecular-weight species of α-Syn and proteinase K-resistant α-Syn aggregates are increased in TG2 Tg /Syn Tg mouse brains when compared with Syn Tg mice [145], while TG2 −/− /Syn Tg mice exhibit the reverse [146].…”

Section: Tg2 In Parkinson's Disease and Dementia With Lewy Bodiesmentioning

confidence: 99%

“…To date, the most important irreversible inhibitor produced by Zedira, ZED1227, has completed a phase II clinical trial for the treatment of celiac disease, with improved symptom and quality-of-life scores [14,15]. ZED1227 shows high potency, with an IC50 of 45 nM and specificity for targeting TG2, but its limitation to cross the blood-brain barrier (BBB) precludes its utility for neurodegenerative diseases [30,211]. More recent efforts in the design or optimization of novel irreversible inhibitors serve as a template for the future development of potent therapeutic tools [202,203,212,213].…”

Section: Irreversible Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Liu,

Mouradian

2024

IJMS

View full text Add to dashboard Cite

Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer’s disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson’s disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington’s disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.

show abstract

Section: Structure and Multifunctional Activities Of Tg2mentioning

confidence: 99%

Section: Tg2 In Parkinson's Disease and Dementia With Lewy Bodiesmentioning

confidence: 99%

Section: Tg2 In Parkinson's Disease and Dementia With Lewy Bodiesmentioning

confidence: 99%

Section: Irreversible Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Liu,

Mouradian

2024

IJMS

View full text Add to dashboard Cite

show abstract

“…This promising molecule warrants further testing in other disease models. In addition, an endogenous enzyme transglutaminase 2 (TG2) (catalyzing α-syn cross-linking and aggregation) was effectively inhibited by cystamine and cysteamine in vitro [ 279 ]. Other compounds reported to affect oligomerization include Bay K-8644, KYP2047, Demeclocycline HCl, Ro 90-7501 and SLS-007 peptides [ 280 , 281 , 282 ].…”

Section: Drugs Targeting α-Synucleinmentioning

confidence: 99%

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Siwecka,

Saramowicz,

Galita

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

show abstract

Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma

Kim,

Kang,

Kim

et al. 2024

Bioorganic Chemistry

View full text Add to dashboard Cite

Targeting transglutaminase 2 as a potential disease modifying therapeutic strategy for synucleinopathies

Cited by 3 publications

References 15 publications

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma

Contact Info

Product

Resources

About