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Protein Disulfide Isomerase and the Endoplasmic Reticulum in Amyotrophic Lateral Sclerosis

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Protein Disulfide Isomerase and the Endoplasmic Reticulum in Amyotrophic Lateral Sclerosis The Journal of Neuroscience, March 17, 2010 • 30(11):3865–3867 • 3865 Journal Club Editor’s Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more infor- mation on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml. Protein Disulfide Isomerase and the Endoplasmic Reticulum in Amyotrophic Lateral Sclerosis Adam K. Walker1,2 1Howard Florey Institute, Florey Neuroscience Institutes, and Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia, and 2Department of Biochemistry, La Trobe University, Bundoora, Victoria 3086, Australia Review of Yang et al. Amyotrophic lateral sclerosis (ALS) is a proteins continue to accumulate. The vitro. Furthermore, the authors showed devastating neurodegenerative disease UPR is activated in motor neurons of the that deletion of the gene encoding reti- primarily affecting motor neurons. No most commonly used ALS model, high- culon-4A,B (Rtn-4A,B, also known as previous family history exists in the ma- expressing mutant SOD1 G93A transgenic NogoA,B) prevents PDI redistribution and jority of cases, but mutations in the gene mice, as early as postnatal day 5, long be- accelerates degeneration and disease pro- encoding superoxide dismutase 1 (SOD1) fore symptom onset at approximately day gression in SOD1 G93A mice. These findings cause ϳ20% of familial disease. Although 90 (Saxena et al., 2009). Additionally, ge- suggest that reticulon expression and PDI the mechanisms causing motor neuron netic ablation of the ER stress-activated localization could be important modulating degeneration in ALS remain unknown, transcription factor X-box-binding protein-1 factors in ALS. recent findings highlight a critical role for significantly delays disease onset and in- Initially, the authors identified that the endoplasmic reticulum (ER) in dis- creases survival in mutant SOD1 mice (Hetz Rtn-4A expression altered the distribu- ease pathogenesis. Protein misfolding in et al., 2009). These results indicate that ER tion of proteins containing a lysine–aspar- the ER lumen can activate signaling trans- stress could be an early event in the patho- tic acid–glutamic acid–leucine (KDEL) duction pathways known collectively as genic cascade in ALS. motif, which is present at the far C termi- the unfolded protein response (UPR), One important UPR-induced chaper- nus of many ER-localized proteins to which occurs in mutant SOD1 models of one is protein disulfide isomerase (PDI). allow receptor-mediated ER retention. ALS (Atkin et al., 2006), and in human PDI is an abundant enzyme that forms, Rtn-4A expression in simian fibroblast sporadic disease (Atkin et al., 2008). breaks, and isomerizes disulfide bonds COS-7 cells, which normally have no de- The UPR attempts to resolve ER stress and is therefore an important cellular de- tectable Rtn-4A, redistributed KDEL pro- by inhibiting protein translation, increas- fense against protein misfolding. PDI is teins from a reticular pattern, reminiscent ing production of chaperone proteins, upregulated before symptom onset in spi- of the normal ER, to a more punctate pat- and enhancing protein degradation; how- nal cords of mutant SOD1 G93A mice and tern (Yang et al., 2009, their Fig. 1). Using ever, cell death is triggered if misfolded rats and in human ALS postmortem tissue antibodies directed against individual (Atkin et al., 2008). Although PDI can be KDEL proteins, the authors showed that protective against mutant SOD1 aggrega- Rtn-4A expression changed PDI distribu- Received Jan. 25, 2010; revised Feb. 4, 2010; accepted Feb. 5, 2010. tion and toxicity, aberrant S-nitrosylation tion to a high degree, whereas other KDEL A.K.W. is supported by an Australian Postgraduate Award and an Aus- tralian Rotary Health scholarship. I thank Dr. Julie Atkin and Prof. Malcolm of critical active site cysteine residues likely proteins, such as Grp94 (glucose-regu- Horne for helpful comments on this manuscript. Related studies in the inactivates the normal protective function lated protein 94), calreticulin, and BiP (Ig Atkin and Horne laboratories were supported in part by National Health of PDI in ALS spinal cords (Walker et al., binding protein), displayed little or no and Medical Research Council of Australia Project Grants 454749 and 2010). change in localization (Yang et al., 2009, 236805, Amyotrophic Lateral Sclerosis Association (United States), Motor Neurone Disease Research Institute of Australia, Bethlehem Griffiths Re- In a recent paper published in The their Fig. 2). Furthermore, expression of search Foundation, and a Henry H. Roth Charitable Foundation Grant for Journal of Neuroscience, Yang et al. (2009) different isoforms of the four mammalian Motor Neurone Disease Research. further investigated the role of PDI in ALS reticulon proteins, namely Rtn-1C, Rtn- Correspondence should be addressed to Adam K. Walker, Florey Neuro- and identified reticulons, a family of inte- 2A, Rtn-3, and Rtn-4C (NogoC), also science Institutes, The University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: [email protected]. gral ER membrane proteins of primarily caused PDI redistribution (Yang et al., DOI:10.1523/JNEUROSCI.0408-10.2010 ill-defined function, as important modu- 2009, their Fig. 3). Therefore, redistribu- Copyright © 2010 the authors 0270-6474/10/303865-03$15.00/0 lators of PDI subcellular localization in tion of PDI to ER subcompartments or 3866 • J. Neurosci., March 17, 2010 • 30(11):3865–3867 Walker • Journal Club other regions within the cell could be a lons and microtubules, could be impor- reticulons in ER stress signaling, whether previously unidentified function of the re- tant for motor neuron survival. neutral, protective, or detrimental, thus re- ticulon protein family. Yang et al. (2009) further confirmed mains uncertain (Teng and Tang, 2008). How do reticulons mediate PDI re- that reticulons cause PDI redistribution in Another unanswered question is whether distribution? Little colocalization was mouse motor neurons in vivo. Genetic de- reticulon-mediated redistribution is spe- observed between PDI and reticulon pro- letion of Rtn-4A,B resulted in a more ho- cific for PDI or involves other ER proteins teins, indicating that changes in PDI lo- mogenous distribution of PDI with fewer not investigated in this study. The authors calization were not mediated by direct PDI puncta in spinal motor neurons com- note that expression of both Rtn-1C and interaction (Yang et al., 2009, their Fig. 3). pared with those of wild-type mice, with- Rtn-4C caused redistribution of the PDI Reticulon involvement in microtubule- out any change in distribution of the ER family member ERp57, albeit to a lesser based intracellular and axonal transport transmembrane protein calnexin (Yang et extent than PDI itself (Yang et al., 2009, processes implicated in many adult-onset al., 2009, their Fig. 5). Conversely, Rtn-4A their supplemental Fig. 1, available at neurodegenerative diseases, including ALS, overexpression in motor neurons increased www.jneurosci.org as supplemental ma- could be one explanation (Morfini et al., PDI puncta formation, again without terial). Upregulation of ERp57 was found 2009). change in calnexin distribution (Yang et al., previously in both SOD1 G93A mice and Interestingly, Rtn-3 is both antero- 2009, their Fig. 5). rats, indicating that other PDI family gradely and retrogradely transported in To demonstrate that reticulon expres- members are involved in disease (Atkin et axons, and overexpression of Rtn-3 causes sion affected ALS disease onset and pro- al., 2006). It is therefore important to an imbalance in axonal cargo transport gression, the authors showed that genetic identify which other ER proteins show al- (Shi et al., 2009). Whether other reticu- deletion of Rtn-4A,B accelerated axonal tered distribution in the reticulon dele- lons are also involved in microtubule- degeneration in spinal cords of transgenic tion and overexpression mice. based transport remains to be seen, but SOD1 G93A-expressing mice (Yang et al., Finally, an issue not directly assessed in mutation of the microtubule-associated 2009, their Fig. 6). Additionally, SOD1 G93A this study is the functional consequences protein mini spindles in Drosophila alters mice with deletion of one or both Rtn-4A,B of PDI redistribution. PDI is highly ex- localization of both PDI and the Dro- alleles reached disease end-stage signifi- pressed in spinal cord motor neurons sophila reticulon protein reticulon like-1 cantly earlier than controls, with a decrease (Atkin et al., 2006) and undergoes aber- (Pokrywka et al., 2009). This suggests that in survival of up to 13 d in Rtn-4A,Bϩ/Ϫ rant posttranslational modification in reticulons affect microtubule-based ax- mice and 20 d in Rtn-4A,BϪ/Ϫ mice (Yang et ALS (Walker et al., 2010), indicating that onal transport and that distribution of al., 2009, their Fig. 8). Motor performance PDI function could affect motor neuron both PDI and reticulons depends on mi- was also decreased and weight loss was ac- survival. Reticulon-mediated PDI redis- crotubule-based transport. celerated in SOD1 G93A mice with Rtn-4A,B tribution could lead to an increase in A second, although not mutually ex- deletion. These results suggest that Rtn- PDI activity as a result of altered protein clusive, explanation
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