Presence of Tissue Transglutaminase in Granular Endoplasmic Reticulum is Characteristic of Melanized Neurons in Parkinson's Disease Brain

Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, the Netherlands.
Brain Pathology (Impact Factor: 3.84). 03/2011; 21(2):130-9. DOI: 10.1111/j.1750-3639.2010.00429.x
Source: PubMed


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.

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Available from: Micha Wilhelmus
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    • "In addition, no colocalization of anti-tTG antibody immunoreactivity with the pathologic lesions characteristic of ADdin particular, senile plaques (SPs), cerebral amyloid angiopathy (CAA), and neurofibrillary tangles (NFTs)dwas observed. On the basis of their findings, Wolf and colleagues concluded that, in contrast to many previous reports including those from our group (Appelt et al., 1996; Bonelli et al., 2002; Citron et al., 2002; Dudek & Johnson, 1993; Johnson et al., 1997; Kim et al., 1999; Miller & Anderton, 1986; Miller & Johnson, 1995; Nemes et al., 2004; Norlund et al., 1999; Selkoe, 2002; Selkoe et al., 1982a, 1982b; Singer et al., 2002; Wang et al., 2008; Wilhelmus et al., 2009, 2011a, 2011b, 2012b; Zhang et al., 1998), tTG is not present in the brain, apart from blood vessels, and is also not associated with the pathologic lesions of AD, in particular SPs, CAA and NFTs. In the discussion section of the article, they suggested that their relatively long postmortem delay differs from the other reports that did find colocalization of tTG with SPs, CAA, and NFTs (Appelt et al., 1996; Citron et al., 2002; de Jager et al., 2013; Dudek & Johnson,1993; Johnson et al.,1997; Kim et al.,1999; Miller & Johnson, 1995; Nemes et al., 2004; Norlund et al., 1999; Selkoe et al., 1982a; Singer et al., 2002; Wilhelmus et al., 2009, 2012b; Zhang et al., 1998) and that this might explain the fact that no association of tTG with the pathological hallmarks of AD was found. "

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    • "However, they have other functions that could be relevant to Parkinson's disease. Calmodulin and -synuclein interact in cells in a calciumdependent manner to regulate dopamine release (Martinez et al., 2003), whereas calreticulin in the endoplasmic reticulum plays a critical role in protein-folding and is associated with transglutaminase , which has been implicated in the formation of -synuclein aggregates in Parkinson's disease brain (Feng et al., 1999; Wilhelmus et al., 2011). The calbindin 1 gene has been identified as a risk factor for Parkinson's disease in a Japanese population, but not in Caucasian patients with Parkinson's disease (Mizuta et al., 2008; Soto-Ortolaza et al., 2010). "
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    • "As such, it is also involved in the folding of newly synthesized proteins and glycoproteins and, together with calnexin (an integral ER membrane chaperone) and PDIA3 (ERp57, an ER protein of 57 kDa; a PDI (protein disulfide-isomerase)-like ER-resident protein), it constitutes the 'calreticulin/calnexin cycle that is responsible for folding and quality control of newly synthesized glycoproteins. In fact, during recent years, CALR has been implicated to play a pivotal role in many biological systems, including functions inside and outside of the ER, indicating that the protein is a multi-process molecule (Gelebart et al., 2005; Gold et al., 2010; Michalak et al., 2009) that might be involved as an ER-resident chaperone in AD and PD (Kudo et al., 2008; Lai et al., 2009; Wilhelmus et al., 2011). PDIA3 itself is an ERresident thiol-disulfide oxidoreductase which is modulating STAT (signal transducer and activator of transcription, also affected upon tianma treatment) signaling from the lumen of the ER together with CALR (Chichiarelli et al., 2010; Coe et al., 2010) that might be affected by PD (Kim-Han and O'Malley, 2007). "
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