The article is interesting and paves the way to new insights on the pathogenic mechanisms of SOD-linked ALS.
The data that are most convincing for us are the studies in transgenic mice: there is a clear correlation between the expression levels of Nogo-A and mouse survival and motor ability; this underlines the critical role of Nogo-A in protecting neurons from SOD1-dependent toxicity.
The PDI redistribution upon Nogo-A overexpression is also interesting, but we think that the pathway that leads to this effect is not clear. Is it mediated by a direct interaction or are other proteins involved? What is the biological significance of PDI puncta within the cell?
The main problem for us is that the link between PDI redistribution and the protective role of Nogo-A in ALS is purely correlative. Although it is possible that Nogo-A protects motor neurons by redistributing PDI, this has not been demonstrated. We would like to know more on how redistributed PDI can prevent motor neuron degeneration.
Since 2002, Nogo isoforms have been suggested as potentially useful biomarkers for ALS diagnosis and prognosis. Recent findings have indicated that disease severity may be correlated with Nogo isoform expression levels in the muscles, although this phenomenon may not be specific for ALS, and occurs also in other forms of myopathies.
Nogo-A’s role in ALS is not clearly understood. Is it just a bystander, does it play a role in aggravating the disease, or does it actually help protect against ALS? A previous report (Jokic et al., 2006) has suggested that Nogo-A may be a causative factor or has a role in disease progression, as the authors found that Nogo-A knockout could increase the survival period of ALS SOD(G86R) mice, while its overexpression destabilized neuromuscular junctions, which would eventually result in motor neuron death.
The paper by Yang et al. (2009) provides a contrasting and interesting role for Nogo-A in ALS. The authors showed that Nogo-A may function to enhance survival in ALS mice by redistributing the endoplasmic reticulum (ER) chaperone, protein disulfide isomerise (PDI), to a subcellular compartment of uncertain identity. In contrast to the earlier report, Yang et al. found that deletion of Nogo-A/B accelerated axonal degeneration of another ALS mutant SOD model, the SOD(G93A) mice. Walker’s commentary (2010) on the Yang paper is very comprehensive, and the author has made several cogent and insightful comments on several aspects of the Yang paper.
In furthering the discussion, I feel that there are two important and interesting aspects to the Yang paper that warrant further investigation by workers in the field. Firstly, from a cell biological perspective, it would be exciting to find out exactly to which subcellular compartment PDI is redistributed. Based on a rather limited marker profile, the authors have ruled out Golgi, endosomes, and vesicles in the autophagy pathway. I doubt that the spots are simply protein aggregates. One possibility is that PDI has been redistributed to specific parts of the ER, such as the ER exit sites or the ER-Golgi intermediate compartment (ERGIC) (Appenzeller-Herzog and Hauri, 2006). PDI has been shown to be functionally inactivated in ALS by S-nitrosylation and as such could no longer be protective against misfolded proteins in disease conditions (Walker et al., 2010). Therefore, could Nogo-A aid in the removal of dysfunctional PDI from the ER, and in doing so, eventually enhance protein folding in ER and hence survival? This, of course, begs the question of how Nogo-A could affect PDI’s redistribution without directly interacting or colocalizing with the latter. It should be noted that all Nogo isoforms are primarily ER residents, and Nogo-A and B have been implicated to act in the modulation of ER morphology and shape (Voeltz et al., 2006). Therefore, Nogo isoform expression levels are likely to influence the dynamics and distribution of ER residents, such as the KDEL signal-containing proteins. How this influence is connected to pathological conditions like ALS should be an interesting line of investigation.
The second, more clinically relevant point is the contrasting results between the studies by Jokic et al. and Yang et al. It would be interesting, if only on a speculative basis, to try to understand how such a discrepancy could arise. There are two notable differences between the mouse models used by the different group of authors. Firstly, the nature of the SOD1 mutation is different (G86R for Jokic et al. and G93A for Yang et al.). Secondly, and perhaps connected to a controversy in the Nogo field (Teng and Tang, 2005), the two studies differ in the Nogo knockout mice used. The model used by Jokic et al. is based on the Nogo knockout generated by Simonen et al. (2003), with parts of nogo exons 2 and 3 and the intron between them deleted. The model used by Yang et al., on the other hand, is based on one reported by Kim et al. (2003), generated by a gene trap insertion that maps near the 5′ end of exon 3. The mice used by Simonen et al. no longer expressed the Nogo-A isoform, but both Nogo-B and Nogo-C, the other two major Nogo isoforms, remained expressed. In fact, there appears to be a compensatory upregulation of Nogo-B in the CNS of the mice used by Simonen et al. The mice used by Kim et al., on the other hand, have both Nogo-A and Nogo-B isoforms deleted. In the initial reports on effects of the respective knockouts on axonal regeneration, the mice used by Kim et al. appeared to have a better enhancement in regenerative capacity. The differences in the nature of SOD1 mutant and Nogo isoform deletion could potentially contribute towards the contrasting conclusions reached by the different authors on the role of Nogo in ALS disease onset and progression. For reasons yet unclear, the Jokic/Simonen mice were less prone to mutant SOD1-induced ALS motor neuron degeneration compared to wild-type control, while the Yang/Kim mice were more disease susceptible compared to wild-type. Further comparative investigations would shed light on the differences between these animals.
Many questions still loom ahead with regard to Nogo-A’s actual role and importance in ALS. Efforts in resolving these questions could make crucial contributions toward the prevention and treatment of the disease.
References:
Appenzeller-Herzog C, Hauri HP.
The ER-Golgi intermediate compartment (ERGIC): in search of its identity and function.
J Cell Sci. 2006 Jun 1;119(Pt 11):2173-83.
PubMed.
Jokic N, Gonzalez de Aguilar JL, Dimou L, Lin S, Fergani A, Ruegg MA, Schwab ME, Dupuis L, Loeffler JP.
The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model.
EMBO Rep. 2006 Nov;7(11):1162-7.
PubMed.
Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM.
Axon regeneration in young adult mice lacking Nogo-A/B.
Neuron. 2003 Apr 24;38(2):187-99.
PubMed.
Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, Christ F, Sansig G, van der Putten H, Schwab ME.
Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury.
Neuron. 2003 Apr 24;38(2):201-11.
PubMed.
Teng FY, Tang BL.
Why do Nogo/Nogo-66 receptor gene knockouts result in inferior regeneration compared to treatment with neutralizing agents?.
J Neurochem. 2005 Aug;94(4):865-74.
PubMed.
Walker AK.
Protein disulfide isomerase and the endoplasmic reticulum in amyotrophic lateral sclerosis.
J Neurosci. 2010 Mar 17;30(11):3865-7.
PubMed.
Walker AK, Farg MA, Bye CR, McLean CA, Horne MK, Atkin JD.
Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis.
Brain. 2010 Jan;133(Pt 1):105-16.
PubMed.
Yang YS, Harel NY, Strittmatter SM.
Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis.
J Neurosci. 2009 Nov 4;29(44):13850-9.
PubMed.
Comments
The article is interesting and paves the way to new insights on the pathogenic mechanisms of SOD-linked ALS.
The data that are most convincing for us are the studies in transgenic mice: there is a clear correlation between the expression levels of Nogo-A and mouse survival and motor ability; this underlines the critical role of Nogo-A in protecting neurons from SOD1-dependent toxicity.
The PDI redistribution upon Nogo-A overexpression is also interesting, but we think that the pathway that leads to this effect is not clear. Is it mediated by a direct interaction or are other proteins involved? What is the biological significance of PDI puncta within the cell?
The main problem for us is that the link between PDI redistribution and the protective role of Nogo-A in ALS is purely correlative. Although it is possible that Nogo-A protects motor neurons by redistributing PDI, this has not been demonstrated. We would like to know more on how redistributed PDI can prevent motor neuron degeneration.
View all comments by Matteo FossatiNational University of Singapore
Since 2002, Nogo isoforms have been suggested as potentially useful biomarkers for ALS diagnosis and prognosis. Recent findings have indicated that disease severity may be correlated with Nogo isoform expression levels in the muscles, although this phenomenon may not be specific for ALS, and occurs also in other forms of myopathies.
Nogo-A’s role in ALS is not clearly understood. Is it just a bystander, does it play a role in aggravating the disease, or does it actually help protect against ALS? A previous report (Jokic et al., 2006) has suggested that Nogo-A may be a causative factor or has a role in disease progression, as the authors found that Nogo-A knockout could increase the survival period of ALS SOD(G86R) mice, while its overexpression destabilized neuromuscular junctions, which would eventually result in motor neuron death.
The paper by Yang et al. (2009) provides a contrasting and interesting role for Nogo-A in ALS. The authors showed that Nogo-A may function to enhance survival in ALS mice by redistributing the endoplasmic reticulum (ER) chaperone, protein disulfide isomerise (PDI), to a subcellular compartment of uncertain identity. In contrast to the earlier report, Yang et al. found that deletion of Nogo-A/B accelerated axonal degeneration of another ALS mutant SOD model, the SOD(G93A) mice. Walker’s commentary (2010) on the Yang paper is very comprehensive, and the author has made several cogent and insightful comments on several aspects of the Yang paper.
In furthering the discussion, I feel that there are two important and interesting aspects to the Yang paper that warrant further investigation by workers in the field. Firstly, from a cell biological perspective, it would be exciting to find out exactly to which subcellular compartment PDI is redistributed. Based on a rather limited marker profile, the authors have ruled out Golgi, endosomes, and vesicles in the autophagy pathway. I doubt that the spots are simply protein aggregates. One possibility is that PDI has been redistributed to specific parts of the ER, such as the ER exit sites or the ER-Golgi intermediate compartment (ERGIC) (Appenzeller-Herzog and Hauri, 2006). PDI has been shown to be functionally inactivated in ALS by S-nitrosylation and as such could no longer be protective against misfolded proteins in disease conditions (Walker et al., 2010). Therefore, could Nogo-A aid in the removal of dysfunctional PDI from the ER, and in doing so, eventually enhance protein folding in ER and hence survival? This, of course, begs the question of how Nogo-A could affect PDI’s redistribution without directly interacting or colocalizing with the latter. It should be noted that all Nogo isoforms are primarily ER residents, and Nogo-A and B have been implicated to act in the modulation of ER morphology and shape (Voeltz et al., 2006). Therefore, Nogo isoform expression levels are likely to influence the dynamics and distribution of ER residents, such as the KDEL signal-containing proteins. How this influence is connected to pathological conditions like ALS should be an interesting line of investigation.
The second, more clinically relevant point is the contrasting results between the studies by Jokic et al. and Yang et al. It would be interesting, if only on a speculative basis, to try to understand how such a discrepancy could arise. There are two notable differences between the mouse models used by the different group of authors. Firstly, the nature of the SOD1 mutation is different (G86R for Jokic et al. and G93A for Yang et al.). Secondly, and perhaps connected to a controversy in the Nogo field (Teng and Tang, 2005), the two studies differ in the Nogo knockout mice used. The model used by Jokic et al. is based on the Nogo knockout generated by Simonen et al. (2003), with parts of nogo exons 2 and 3 and the intron between them deleted. The model used by Yang et al., on the other hand, is based on one reported by Kim et al. (2003), generated by a gene trap insertion that maps near the 5′ end of exon 3. The mice used by Simonen et al. no longer expressed the Nogo-A isoform, but both Nogo-B and Nogo-C, the other two major Nogo isoforms, remained expressed. In fact, there appears to be a compensatory upregulation of Nogo-B in the CNS of the mice used by Simonen et al. The mice used by Kim et al., on the other hand, have both Nogo-A and Nogo-B isoforms deleted. In the initial reports on effects of the respective knockouts on axonal regeneration, the mice used by Kim et al. appeared to have a better enhancement in regenerative capacity. The differences in the nature of SOD1 mutant and Nogo isoform deletion could potentially contribute towards the contrasting conclusions reached by the different authors on the role of Nogo in ALS disease onset and progression. For reasons yet unclear, the Jokic/Simonen mice were less prone to mutant SOD1-induced ALS motor neuron degeneration compared to wild-type control, while the Yang/Kim mice were more disease susceptible compared to wild-type. Further comparative investigations would shed light on the differences between these animals.
Many questions still loom ahead with regard to Nogo-A’s actual role and importance in ALS. Efforts in resolving these questions could make crucial contributions toward the prevention and treatment of the disease.
References:
Appenzeller-Herzog C, Hauri HP. The ER-Golgi intermediate compartment (ERGIC): in search of its identity and function. J Cell Sci. 2006 Jun 1;119(Pt 11):2173-83. PubMed.
Jokic N, Gonzalez de Aguilar JL, Dimou L, Lin S, Fergani A, Ruegg MA, Schwab ME, Dupuis L, Loeffler JP. The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Rep. 2006 Nov;7(11):1162-7. PubMed.
Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron. 2003 Apr 24;38(2):187-99. PubMed.
Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, Christ F, Sansig G, van der Putten H, Schwab ME. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron. 2003 Apr 24;38(2):201-11. PubMed.
Teng FY, Tang BL. Why do Nogo/Nogo-66 receptor gene knockouts result in inferior regeneration compared to treatment with neutralizing agents?. J Neurochem. 2005 Aug;94(4):865-74. PubMed.
Walker AK. Protein disulfide isomerase and the endoplasmic reticulum in amyotrophic lateral sclerosis. J Neurosci. 2010 Mar 17;30(11):3865-7. PubMed.
Walker AK, Farg MA, Bye CR, McLean CA, Horne MK, Atkin JD. Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis. Brain. 2010 Jan;133(Pt 1):105-16. PubMed.
Yang YS, Harel NY, Strittmatter SM. Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis. J Neurosci. 2009 Nov 4;29(44):13850-9. PubMed.
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