Transglutaminase 2 as a therapeutic target for neurological conditions

ABSTRACT

Introduction

Transglutaminase 2 (TG2) has been implicated in numerous neurological conditions, including neurodegenerative diseases, multiple sclerosis, and CNS injury. Early studies on the role of TG2 in neurodegenerative conditions focused on its ability to ‘crosslink’ proteins into insoluble aggregates. However, more recent studies have suggested that this is unlikely to be the primary mechanism by which TG2 contributes to the pathogenic processes. Although the specific mechanisms by which TG2 is involved in neurological conditions have not been clearly defined, TG2 regulates numerous cellular processes through which it could contribute to a specific disease. Given the fact that TG2 is a stress-induced gene and elevated in disease or injury conditions, TG2 inhibitors may be useful neurotherapeutics.

Areas covered

Overview of TG2 and different TG2 inhibitors. A brief review of TG2 in neurodegenerative diseases, multiple sclerosis and CNS injury and inhibitors that have been tested in different models. Database search: https://pubmed.ncbi.nlm.nih.gov prior to 1 July 2021.

Expert Opinion

Currently, it appears unlikely that inhibiting TG2 in the context of neurodegenerative diseases would be therapeutically advantageous. However, for multiple sclerosis and CNS injuries, TG2 inhibitors may have the potential to be therapeutically useful and thus there is rationale for their further development.

KEYWORDS:

• Transglutaminase 2
• neurodegenerative diseases
• Alzheimer’s disease
• Huntington’s disease
• Parkinson’s disease
• multiple sclerosis
• CNS injury
• TG2 inhibitors

Article Highlights

• Transglutaminase 2 (TG2) is a multifunctional protein that exhibits dramatically different ‘open’ (‘active’) and ‘closed’ (‘inactive’) conformations, which is a key factor in determining the function of TG2, independent of transamidase activity.

• Although TG2 can crosslink disease relevant proteins in vitro, there is a growing awareness that TG2 may be mediating pathological processes independent of its ability to catalyze the formation of isopeptide bonds.

• Cysteamine, a non-specific competitive inhibitor of transglutaminases, protects neurons from mutant huntingtin-induced toxicity, bud did not demonstrate efficacy in a randomized, double-blind, placebo-controlled trial in HD patients.

• Overall, it appears unlikely that inhibiting TG2 in the context of Huntington’s disease Alzheimer’s disease or Parkinson’s disease would be therapeutically advantageous.

• There is support for considering cell impermeant TG2 inhibitors that function primarily by blocking TG2–fibronectin interaction for the treatment of multiple sclerosis.

• Specific inhibitors that irreversibly lock TG2 into an open conformation may have potential for the treatment of CNS injury.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Work from the GVW Johnson laboratories was funded by: NYS SCIRB grant [DOH01-C34458GG] (GVWJ). JW Keillor is supported by CIHR grant [PJT-162180].