26 March 2010. Researchers recently pegged the reticulon Nogo-A as a protective factor in amyotrophic lateral sclerosis. The authors, from the Yale University School of Medicine in New Haven, Connecticut, published their results in the November 4, 2009, Journal of Neuroscience. This month, in the March 17 issue, the journal revisited the finding with a review by Adam Walker of the University of Melbourne in Parkville, Australia. ARF is extending that discussion by soliciting reader comments.
The Yale researchers, joint first authors Yvonne Yang and Noam Harel, and senior author Stephen Strittmatter, investigated the role of Nogo-A in cell culture and ALS model mice. Nogo-A inhibits axon outgrowth, but as a member of the reticulon family of endoplasmic reticulum (ER) membrane proteins, it might also contribute to ER morphology. Nogo-A is upregulated in both human ALS cases and ALS model mice (Dupuis et al., 2002).
Strittmatter and colleagues found that Nogo-A controls distribution of the chaperone protein disulfide isomerase (PDI). This ER-resident enzyme makes and breaks disulfide bonds. In cells that lack Nogo-A, such as the COS-7 kidney cells used in the study, PDI shows a homogeneous, cytoplasmic distribution. When the scientists added the Nogo-A gene, they found that PDI was reorganized in a punctate pattern. The researchers were unable to determine the identity of these puncta; they could be protein aggregates, vesicles, or another kind of intracellular compartment.
PDI is normally punctate in mouse spinal motor neurons. It becomes more homogeneous in Nogo-A knockout mice, and more condensed in mice that overexpress Nogo-A. The researchers also found that Nogo-A deletion curtailed survival of ALS model mice by up to three weeks, and suggest that a drug that increases PDI puncta could be an ALS therapy.
As Walker notes in his commentary, the Strittmatter data would predict that overexpression of Nogo-A would protect mice against ALS pathology. Such an experiment would clinch the hypothesis, he writes.
Strittmatter and colleagues found that the unfolded protein response was not upregulated in the presence of Nogo-A, suggesting that this common stress pathway is not the explanation for the protective effect. Nogo-A did not colocalize with PDI puncta, so it must govern PDI localization indirectly. The authors suggest that Nogo-A might influence ER shape, as the related atlastins do, and thus reorganize PDI (see ARF related news story on Hu et al., 2009 and Orso et al., 2009). Alternatively, Walker speculates, Nogo-A might adjust PDI placement by restructuring the microtubule network.
ARF wants to know what you think about this research. How could reticulons such as Nogo-A affect ALS pathology? Could this lead to a treatment? We invite comments from seasoned investigators and young researchers. Elisa Fasana and Matteo Fossati, of the CNR Neuroscience Institute in Milan, Italy, get things going. They find the mouse data convincing, but have questions about the exact role of Nogo-A (see comments below). Felicia Teng of the National University of Singapore comments on the potential identity of the PDI puncta and speculates why Strittmatter’s results conflict with previous work.—Amber Dance.
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. Abstract
Walker AK. Protein disulfide isomerase and the endoplasmic reticulum in amyotrophic lateral sclerosis. J Neurosci. 2010 Mar 17;30(11):3865-7. Abstract