Transglutaminase 2 ablation leads to defective function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders

J Neurochem. 2007 Jan;100(1):36-49. doi: 10.1111/j.1471-4159.2006.04140.x. Epub 2006 Oct 25.


Transglutaminase 2 (TG2) represents the most ubiquitous isoform belonging to the TG family, and has been implicated in the pathophysiology of basal ganglia disorders, such as Parkinson's disease and Huntington's disease. We show that ablation of TG2 in knockout mice causes a reduced activity of mitochondrial complex I associated with an increased activity of complex II in the whole forebrain and striatum. Interestingly, TG2-/- mice were protected against nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is converted in vivo into the mitochondrial complex I inhibitor, 1-methyl-4-phenyl-pyridinium ion. In contrast, TG2-/- mice were more vulnerable to nigrostriatal damage induced by methamphetamine or by the complex II inhibitor, 3-nitropropionic acid. Proteomic analysis showed that proteins involved in the mitochondrial respiratory chain, such as prohibitin and the beta-chain of ATP synthase, are substrates for TG2. These data suggest that TG2 is involved in the regulation of the respiratory chain both in physiology and pathology, contributing to set the threshold for neuronal damage in extrapyramidal disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / metabolism
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Adenosine Triphosphate / metabolism
  • Animals
  • Basal Ganglia Diseases / genetics*
  • Basal Ganglia Diseases / physiopathology*
  • Biogenic Monoamines / metabolism
  • Blotting, Western / methods
  • Body Weight / drug effects
  • Corpus Striatum / drug effects
  • Disease Models, Animal
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Electron Transport Complex I / metabolism*
  • Electron Transport Complex II / metabolism
  • GTP-Binding Proteins / deficiency*
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry / methods
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Diseases / etiology
  • Mitochondrial Diseases / pathology*
  • Neurons / pathology*
  • Piperazines / pharmacokinetics
  • Protein Glutamine gamma Glutamyltransferase 2
  • Time Factors
  • Transglutaminases / deficiency*
  • Tyrosine 3-Monooxygenase / metabolism


  • Biogenic Monoamines
  • Dopamine Plasma Membrane Transport Proteins
  • Glial Fibrillary Acidic Protein
  • Piperazines
  • Adenosine Triphosphate
  • 1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Electron Transport Complex II
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins
  • Electron Transport Complex I