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Pathogenesis of Inclusion Bodies in (CAG) n /Q n ‐Expansion Diseases with Special Reference to the Role of Tissue Transglutaminase and to Selective Vulnerability
Author(s) -
Cooper Arthur J. L.,
Sheu KwanFu Rex,
Burke James R.,
Strittmatter Warren,
Gentile Vittorio,
Peluso Gianfranco,
Blass John P.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720889.x
Subject(s) - tissue transglutaminase , cytosol , huntington's disease , pathogenesis , biology , inclusion bodies , trinucleotide repeat expansion , neurodegeneration , microbiology and biotechnology , enzyme , human brain , biochemistry , neuroscience , disease , gene , pathology , immunology , medicine , recombinant dna , allele
: At least eight neurodegenerative diseases, includingHuntington disease, are caused by expansions in (CAG) n repeats inthe affected gene and by an increase in the size of the correspondingpolyglutamine domain in the expressed protein. A hallmark of several of thesediseases is the presence of aberrant, proteinaceous aggregates in the nucleiand cytosol of affected neurons. Recent studies have shown that expandedpolyglutamine (Q n ) repeats are excellent glutaminyl‐donorsubstrates of tissue transglutaminase, and that the substrate activityincreases with increasing size of the polyglutamine domain. Tissuetransglutaminase is present in the cytosol and nuclear fractions of braintissue. Thus, the nuclear and cytosolic inclusions in Huntington disease maycontain tissue transglutaminase‐catalyzed covalent aggregates. The(CAG) n /Q n ‐expansion diseases are classic examples ofselective vulnerability in the nervous system, in which certaincells/structures are particularly susceptible to toxic insults. Quantitativedifferences in the distribution of the brain transglutaminase(s) and itssubstrates, and in the activation mechanism of the brain transglutaminase(s),may explain in part selective vulnerability in a subset of neurons in(CAG) n ‐expansion diseases, and possibly in other neurodegenerative disease. If tissue transglutaminase is found to be essential for development of pathogenesis, then inhibitors of this enzyme may be of therapeutic benefit.