. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 2009 Oct 1;23(19):2294-306. PubMed.

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  1. This is an excellent paper highlighting the importance of ER stress and related genes in motor neuron survival. The authors are able to uncover a previously ill-defined connection between one of the essential ER signaling arms (IRE/XBP-1) and an essential cellular function, autophagy. In this work, they define novel pathways by which molecular mechanisms underlying both fALS, and also importantly, sALS, could lead to motor neuron death. As happens in many other examples of pathogenesis, a physiological response (increased ER stress) can led to pathology exacerbation (lack of autophagic response). If this mechanism is consistently tested in other SOD mutants as well as other ALS models, the resulting outcome could shed light upon the development of novel therapeutic approaches.

    Perhaps more interestingly, and as discussed by the authors, ALS pathology shares protein aggregation with other neurodegenerative diseases, such as Alzheimer’s and many others. Is the potential protective role of XBP downregulation also applicable to those diseases? The role of XBPs as a pro-aggregator agent is also interesting. What could be the pathways implicated after XBP? Is XBP-induced ERAD upregulation instrumental in this? Results of the authors suggest that EDEM or other proteins implicated in ERAD could be novel targets of therapeutics. Thus, paradoxically, ERAD impairment would lead to enhanced clearance of misfolded proteins. This could be also related to the described protective role of protein aggregates. This is so if we consider that those aggregates, depending on their cellular location, may actually decrease the chances for XBP activation.

    On the other hand, overall results show a dark side of XBP-driven responses. One wonders if viability of the cells is affected by downregulation of XBPs. It seems that it isn't in control conditions, but what about ER stress conditions? If one considers that mutant SOD leads to ER stress, and XBP downregulation enhances survival in those conditions, then XBP expression should have another important regulatory function in these cells. Otherwise, it would not have been evolutionarily advantageous to conserve this pathway. In addition to this, it is clear that XBP downregulation protects cells against nutrient starvation-induced cell death. This, when added to the lack of observable pathological phenotype of XBP downregulation in neuronal cells, strongly suggests that overall activation of UPR may not always be beneficial.

    It is also interesting that glia appear not to be affected by XBP downregulation in vivo. This is puzzling, as many other researchers have stressed the importance of the neuronal-muscle-glia crosstalk in the pathogenesis of the disease. Thus, this study puts the focus on motor neuron cell biology as a major contributor to fALS.

    Finally, as the authors clearly express, gender matters. As in many other diseases or physiological conditions, females seem to have natural advantages. Though it may be very speculative and naive, those results fit with the hypothesis of ALS as an accelerated aging phenomenon restricted to motor neurons: females, when compared with males of equal chronological age, exhibit decreased levels of several biomarkers of aging, finally resulting in increased lifespan. Obviously, research into the biological determinants (either chromosomal or endocrine) of gender in ALS could also open novel paths for finding a cure for this disease.

    View all comments by Manuel Portero