title: Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain.
abstract: Parkinson's disease (PD) is characterized by the accumulation of α-synuclein aggregates and degeneration of melanized neurons. The tissue transglutaminase (tTG) enzyme catalyzes molecular protein cross-linking. In PD brain, tTG-induced cross-links have been identified in α-synuclein monomers, oligomers and α-synuclein aggregates. However, whether tTG and α-synuclein occur together in PD affected neurons remains to be established. Interestingly, using immunohistochemistry, we observed a granular distribution pattern of tTG, characteristic of melanized neurons in PD brain. Apart from tTG, these granules were also positive for typical endoplasmic reticulum (ER)-resident chaperones, that is, protein disulphide isomerase, ERp57 and calreticulin, suggesting a direct link to the ER. Additionally, we observed the presence of phosphorylated pancreatic ER kinase (pPERK), a classical ER stress marker, in tTG granule positive neurons in PD brain, although no subcellular colocalization of tTG and pPERK was found. Our data therefore suggest that tTG localization to granular ER compartments is specific for stressed melanized neurons in PD brain. Moreover, as also α-synuclein aggregates were observed in tTG granule positive neurons, these results provide a clue to the cellular site of interaction between α-synuclein and tTG.
authors: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, the Netherlands. m.wilhelmus@vumc.nl
authors: Micha M M
authors: MM
authors: Wilhelmus
authors: Robin
authors: R
authors: Verhaar
authors: Gerda
authors: G
authors: Andringa
authors: John G J M
authors: JG
authors: Bol
authors: Patrick
authors: P
authors: Cras
authors: Ling
authors: L
authors: Shan
authors: Jeroen J M
authors: JJ
authors: Hoozemans
authors: Benjamin
authors: B
authors: Drukarch
mesh_terms: D000368:Aged; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D005260:Female; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D019204:GTP-Binding Proteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051844:alpha-Synuclein; D019892:eIF-2 Kinase