Scrg1 is induced in TSE and brain injuries, and associated with autophagy

Abstract

We have previously identified Scrg1, a gene with increased cerebral mRNA levels in transmissible spongiform encephalopathies (TSE) such as scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. In this study, Scrg1-immunoreactive cells, essentially neurons, were shown to be widely distributed throughout the brain of scrapie-infected mice, while only rare and weakly immunoreactive cells could be detected in the brain of non-infected normal mice. Induction of the protein was confirmed by Western blot analysis. At the ultrastructural level, Scrg1 protein was associated with dictyosomes of the Golgi apparatus and autophagic vacuoles in the central neurons of the scrapie-infected mice. These results suggested a role for Scrg1 in the pathological changes observed in TSE. We have generated transgenic mice specifically expressing Scrg1 in neurons. No significant differences in the time course of the disease were detected between transgenic and non-transgenic mice infected with scrapie prions. However, tight association of Scrg1 with autophagic vacuoles was again observed in brain neurons of infected transgenic mice. High levels of the protein were also detected in degenerating Purkinje cells of Ngsk Prnp 0/0 mice overexpressing the Prnd gene coding for doppel, a neurotoxic paralogue of the prion protein. Furthermore, induction of Scrg1 protein was observed in the brain of mice injured by canine distemper virus or gold thioglucose treatment. Taken together, our results indicate that Scrg1 is associated with neurodegenerative processes in TSE, but is not directly linked to dysregulation of prion protein.

Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells

“…In addition, stimulator of chondrogenesis 1/ scrapie responsive gene 1 (SCRG1) expression is increased in the autophagic vacuoles of neurons from scrapie-infected mice. 31 Recently, it is reported that autophagy induction achieved by pharmacological autophagy inducers, such as trehalose or lithium, can reduce PrP Sc expression in persistently prion-infected neuronal cells. 32,33 Interestingly, the ectopic overexpression of PrP protein 2 (dublet)/PrP-like protein doppel (PRND) in PrP C -deficient central neurons of Ngsk prion protein-deficient (NP 0/0 ) mice showed that the expression levels of SCRG1 and the autophagic markers LC3B-II and sequestosome 1 (SQSTM1)/ p62 were increased both before and during Purkinje cell death, whereas the mRNA expression levels of Lc3b and Sqstm1/p62 remained stable.…”

Cellular pathogenesis in prion diseases

“…On the basis of these studies, Liberski et al have suggested that autophagy plays a major role in TSE and may even participate in the spongiform changes [68]. At the molecular level, Dron et al [33,34], have shown that the Scrg1 gene was upregulated in TSE. This gene encodes a protein associated with the Golgi apparatus as well as with autophagic vacuoles of degenerative neurons.…”

“…This gene encodes a protein associated with the Golgi apparatus as well as with autophagic vacuoles of degenerative neurons. The authors suggest that Scrg1 is involved in the host response to stress and/or the death of neurons and could be used to follow autophagic events [33,34]. However, increased numbers of autophagosomes/autophagic vacuoles are seen in a variety of physiological and pathological states in the nervous system.…”

Autophagy, Prion Infection and their Mutual Interactions

“…This gene was up-regulated in brains of scrapie prion-and BSE-infected mice and in brains of patients with sporadic CJD (Dandoy- Dron et al, 2000;Dandoy-Dron et al, 1998;Dron et al, 1998). In the CNS of prion-infected mice up-regulated Scrg1 was associated with autophagic vacuoles which were observed at the terminal stage of disease (Dron et al, 2005). Consequently, it was suggested that Scrg1 might be useful as a marker for neuronal autophagy in prion diseases (Dron et al, 2006).…”