Transglutaminase is linked to neurodegenerative diseases.

Transglutaminase catalyzes a covalent bond between peptide-bound glutamine residues and either lysine-bound peptide residues or mono- or polyamines. Multiple lines of evidence suggest that transglutaminase is involved in neurodegenerative diseases including Alzheimer disease, progressive supranuclear palsy, Huntington disease (HD), and Parkinson disease. In all of the neurodegenerative diseases examined to date, transglutaminase enzyme activity is upregulated in selectively vulnerable brain regions, transglutaminase proteins are associated with inclusion bodies characteristic of the diseases, and prominent proteins in the inclusion bodies are modified by transglutaminase enzymes. These prominent proteins in the inclusion bodies, including tau, alpha-synuclein, and huntingtin protein, are modified by transglutaminase in vitro and alpha-synuclein and huntingtin protein are modified in cells in culture. Similar changes in transglutaminase and transglutaminase-modified proteins are replicated in transgenic mouse models of the neurodegenerative diseases, including Huntington disease and progressive supranuclear palsy. Lastly, inhibition of transglutaminase either via drug treatments or molecular approaches is beneficial for the treatment of HD transgenic mice but has yet to be explored for the other neurodegenerative diseases. Further research is needed to determine the specific role(s) that transglutaminase plays in the pathophysiology of neurodegenerative diseases with possible implications for transglutaminase as a therapeutic target.