Transglutaminase-mediated crosslinking of neural proteins in Alzheimer's disease and other primary dementias

Mónika Sárvári, L. Fésüs, Zoltán Nemes

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The formation of insoluble protein deposits is a common hallmark of most neurodegenerative diseases. The disease-specific lesions arise from pathogenic modifications of proteins or defects of their breakdown. Transglutaminases posttranslationally modify proteins by transamidation of specific protein-bound glutamines to specific protein-bound lysines. This action results in the formation of covalent crosslinks between proteins, a modification likely to have profound effects on nerve cell function. Crosslinking of proteins via Nε (γ-glutamyl)lysine bonds by transglutaminases has been described in in vitro and animal models of neuron loss. Recent findings provided evidence that dysregulation of transglutaminase activity may contribute to the pathology of various neurodegenerative diseases, including polyglutamine expansion diseases and primary neurodegenerative dementias, the prototype of which is Alzheimer's disease (AD). Transglutaminase activity and expression was shown to be elevated in AD and Huntington's disease (HD) compared to age-matched controls by several studies. Further, crosslinks have been found to colocalize with neurofibrillary tangles characteristic of Alzheimer's pathology by immunocytochemistry. Recent data showed increased crosslink concentrations in the cerebrospinal fluid of HD patients. A series of studies from our laboratory showed that elevated crosslink concentrations in cerebrospinal fluid are characteristic of AD as well as other related dementias associated with the formation of intraneural inclusions. Although many issues remain to be addressed to establish a definitive model for the formation of specific histopathological lesions, crosslinking proteins by transglutaminases offers a plausible explanation for the stabilization of noxious protein aggregates and may reveal a common pathogenic mechanism in various primary neurodegenerative diseases.

Original languageEnglish
Pages (from-to)458-472
Number of pages15
JournalDrug Development Research
Volume56
Issue number3
DOIs
Publication statusPublished - Jul 1 2002

Fingerprint

Transglutaminases
Crosslinking
Dementia
Alzheimer Disease
Neurodegenerative diseases
Neurodegenerative Diseases
Proteins
Cerebrospinal fluid
Huntington Disease
Pathology
Lysine
Neurons
Cerebrospinal Fluid
Neurofibrillary Tangles
Glutamine
Animals
Deposits
Animal Models
Stabilization
Immunohistochemistry

Keywords

  • Apoptosis
  • Neurodegeneration
  • Tau protein
  • Transglutaminase

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Transglutaminase-mediated crosslinking of neural proteins in Alzheimer's disease and other primary dementias. / Sárvári, Mónika; Fésüs, L.; Nemes, Zoltán.

In: Drug Development Research, Vol. 56, No. 3, 01.07.2002, p. 458-472.

Research output: Contribution to journalArticle

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