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Cross‐linking of ubiquitin, HSP27, parkin and α‐synuclein by γ‐glutamyl‐ε‐lysine bonds in Alzheimer's neurofibrillary tangles
Author(s) -
Nemes Zoltán,
Devreese Bart,
Steinert Peter M.,
Beeumen Jozef Van,
Fésüs László
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1493fje
Subject(s) - chemistry , ubiquitin , senile plaques , protein aggregation , lysine , proteasome , hsp27 , tau protein , neurofilament , parkin , amyloid (mycology) , microbiology and biotechnology , biochemistry , alzheimer's disease , biology , heat shock protein , hsp70 , parkinson's disease , medicine , immunohistochemistry , immunology , inorganic chemistry , disease , amino acid , gene
The accumulation of misfolded proteins in intracellular inclusions is a generic feature of neurodegenerative disorders. Although heavily ubiquitylated, the aggregated proteins are not degraded by the proteasomes. A possible reason for this phenomenon may be a modification of deposited proteins by transglutaminases forming γ‐glutamyl‐ε‐lysine (GGEL) cross‐links between distinct proteins. Here, we show that the frequency of GGEL cross‐links is an order of magnitude higher in Alzheimer's brain cortex than in age‐matched or younger controls. This difference is due to the accumulation of GGEL cross‐links in ubiquitin‐immunopositive protein particles present in both Alzheimer's brains and those from aged individuals. The highly cross‐ linked protein aggregates show immunoreactivity to antibodies against tau and neurofilament proteins, and partially also to α‐synuclein, indicating that these structures are inherent in Alzheimer's neurofibrillary tangles and Lewy bodies. Using mass sequence analysis, we identified the same six pairs of peptide sequences cross‐linked in both senile and Alzheimer's specimens: Gln 31 and Gln 190 of HSP27 protein are cross‐linked with Lys 29 and Lys 48 of ubiquitin and HSP27 therefore may cross‐link two (poly)ubiquitin chains. One lysine residue of parkin and one of α‐synuclein were also found to be cross‐linked. The data suggest that cross‐linking of (poly)ubiquitin moieties via HSP27 may have a role in the stabilization of the intraneuronal protein aggregates by interference with the proteasomal elimination of unfolded proteins.