Amino Acids

, Volume 38, Issue 2, pp 653–658 | Cite as

Critical role of transglutaminase and other stress proteins during neurodegenerative processes

  • Daniela Caccamo
  • Monica Currò
  • Salvatore Condello
  • Nadia Ferlazzo
  • Riccardo Ientile
Review Article


Proteolytic stress, resulting from the intracellular accumulation of misfolded or aggregated proteins, which exceed the capacity of the ubiquitin–proteasome system to degrade them, plays a relevant role in neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s chorea. Most of toxic protein aggregates are characterised by the presence of isopeptide bonds (cross-links) catalysed by transglutaminase activity; further, several disease-specific proteins—tau, amyloid-beta, alpha-synuclein, huntingtin—are in vitro and/or in vivo substrates of transglutaminase 2. These findings suggest an important role for transglutaminase 2-mediated cross-linking reactions in neurodegeneration. Therefore, the use of transglutaminase activity inhibitors could ameliorate neuronal cell death. New therapeutic perspectives also arise from the possibility to prevent or reduce protein aggregation by enhancing the activation of heat shock proteins, which have been shown to be potent suppressors of neurodegeneration in cell cultures/animal models. Interestingly, some heat shock proteins have been shown to be in vitro or in vivo cross-linked by transglutaminase 2. These observations seem to suggest that transglutaminase activity could be involved in the stabilization of intracellular protein aggregates by interfering with proteasomal degradation of misfolded proteins. Further studies are needed to validate leading hypotheses and to open new prospects for developing therapeutic tools.


Transglutaminases Tissue transglutaminase Heat shock proteins Protein aggregates Neurodegenerative diseases 



Alzheimer’s disease


Parkinson’s disease


Amyotrophic lateral sclerosis


Cerebrospinal fluid


Extracellular matrix




Huntington’s chorea


Heat shock proteins

NF-kappa B

Nuclear factor-kappa B




Retinoic acid


Spinocerebellar ataxia


Spinobulbar muscular atrophy




Tissue transglutaminase


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Daniela Caccamo
    • 1
  • Monica Currò
    • 1
  • Salvatore Condello
    • 1
  • Nadia Ferlazzo
    • 1
  • Riccardo Ientile
    • 1
  1. 1.Department of Biochemical, Physiological and Nutritional SciencesPoliclinico Universitario, University of MessinaMessinaItaly

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