title: Increase in endoplasmic reticulum-associated tissue transglutaminase and enzymatic activation in a cellular model of Parkinson's disease.
abstract: Parkinson's disease (PD) is characterized by accumulation of α-synuclein aggregates and degeneration of melanized, catecholaminergic neurons. The tissue transglutaminase (tTG) enzyme catalyzes molecular protein cross-linking. In PD, tTG levels are increased and cross-linking has been identified as an important factor in α-synuclein aggregation. In our quest to link tTGs distribution in the human brain to the hallmarks of PD pathology, we recently reported that catecholaminergic neurons in PD disease-affected brain areas display typical endoplasmic reticulum (ER) granules showing tTG immunoreactivity. In the present study, we set out to elucidate the nature of the interaction between tTG and the ER in PD pathogenesis, using retinoic-acid differentiated SH-SY5Y cells exposed to the PD-mimetic 1-methyl-4-phenylpyridinium (MPP(+)). Alike our observations in PD brain, MPP(+)-treated cells displayed typical TG-positive granules, that were also induced by other PD mimetics and by ER-stress inducing toxins. Additional immunocytochemical and biochemical investigation revealed that tTG is indeed associated to the ER, in particular at the cytoplasmic face of the ER. Upon MPP(+) exposure, additional recruitment of tTG toward the ER was found. In addition, we observed that MPP(+)-induced tTG activity results in transamidation of ER membrane proteins, like calnexin. Our data provide strong evidence for a, so far unrecognized, localization of tTG at the ER, at least in catecholaminergic neurons, and suggests that in PD activation of tTG may have a direct impact on ER function, in particular via post-translational modification of ER membrane proteins.
authors: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors: Robin
authors: R
authors: Verhaar
authors: Benjamin
authors: B
authors: Drukarch
authors: John G J M
authors: JG
authors: Bol
authors: Cornelis A M
authors: CA
authors: Jongenelen
authors: René J P
authors: RJ
authors: Musters
authors: Micha M M
authors: MM
authors: Wilhelmus
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D011503:Transglutaminases / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014415:Tunicamycin / Q000378:metabolism
chemical_list: D037282:Calreticulin; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; C416508:GAN protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D014415:Tunicamycin; D037281:Calnexin; D014212:Tretinoin; D019284:Thapsigargin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011503:Transglutaminases; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human