In at least some forms of amyotrophic lateral sclerosis, as in other neurodegenerative diseases, neurons become clogged with aggregated, misfolded proteins. It seems logical that the cell would turn to the endoplasmic reticulum and its unfolded protein response (UPR) pathway to mitigate this circumstance. In a Genes and Development paper published online September 17, researchers report that when they perturbed the unfolded protein response, expecting to exacerbate ALS pathology, they increased autophagy. What’s more, the intracellular digestion of mutant aggregates was protective in both cell culture and mouse models.

“Most of the studies linking protein misfolding and ER stress were just correlative,” said lead author Claudio Hetz of the University of Chile in Santiago. With Laurie Glimcher of Harvard University, Hetz set out to determine whether the ER stress response was beneficial, harmful, or neutral in the case of neurodegenerative disease. The researchers focused their attention on X-box-binding protein-1 (XBP-1), a highly conserved transcription factor that regulates genes for protein folding and the UPR. They thought that without XBP-1, the UPR would suffer and cells would be more susceptible to the effects of mutant superoxide dismutase 1 (SOD1), which is responsible for some familial forms of ALS. Not so: “Everything was the opposite of what we expected,” Hetz said.

In a motor neuron cell line expressing mutant human SOD1 and treated with RNA interference for XBP-1, fewer cells exhibited mSOD1 aggregates and there was less detergent-insoluble mSOD1 than in untreated cells. Applying inhibitors of either the proteasome or autophagy to these cells, Hetz determined that autophagy was responsible for the reduction in mSOD1 aggregation. The XBP-1 knockdown cells also had more autophagosomes than did control cells.

When the researchers deleted XBP-1 in the nervous system of mSOD1 mice, ALS symptoms began later. Female mice survived an average of 22 days longer than control mSOD1 mice, although males received no benefit. Histology showed more autophagosomes in the spinal cords of double mutant mice, and some females had almost no mSOD1 aggregates at all. This gender difference in mice mirrors the situation in people: men are more likely to suffer from ALS than are women. The reason remains a “black box,” Hetz said; perhaps hormones are involved. The researchers also examined a handful of human postmortem spinal cord samples, and found upregulation of both the UPR and autophagy.

XBP-1’s role in repressing autophagy could be direct or indirect. Hetz suggested that the UPR and autophagy might balance each other, and when one pathway is diminished, the other rises. The work suggests that increasing autophagy could become a drug development target for ALS. Hetz suggested that drugs might boost the response; Glimcher noted that it might also be possible to inhibit XBP-1.

Autophagy has also been linked to Alzheimer (e.g., see ARF related news story on Pickford et al., 2008; Cataldo et al., 1996; Yang et al., 2009) and Huntington and Parkinson diseases (see ARF related news story and Yu et al., 2009). Hetz is now studying XBP-1 knockdown in models of these three diseases.—Amber Dance.

Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM, Brown RH, Glimcher LH. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 2009 Sep 17. Abstract


Make a Comment

To make a comment you must login or register.

Comments on this content

  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.


News Citations

  1. Autophagy Regulator Helps Neurons Stomach Excess Aβ, Resist AD
  2. New Targets for Neurodegenerative Diseases: Autophagy and More

Paper Citations

  1. . The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.
  2. . Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci. 1996 Jan;16(1):186-99. PubMed.
  3. . Monitoring autophagy in Alzheimer's disease and related neurodegenerative diseases. Methods Enzymol. 2009;453:111-44. PubMed.
  4. . Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol. 2009 Aug;175(2):736-47. PubMed.
  5. . 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.

Further Reading


  1. . Review: autophagy in neurodegeneration: firefighter and/or incendiarist?. Neuropathol Appl Neurobiol. 2009 Oct;35(5):449-61. PubMed.
  2. . Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy. 2008 Apr;4(3):290-3. PubMed.
  3. . 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.
  4. . Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain. 2007 Dec;130(Pt 12):3111-23. PubMed.
  5. . Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6025-30. PubMed.
  6. . ER stress and neurodegenerative diseases. Cell Death Differ. 2006 Mar;13(3):385-92. PubMed.

Primary Papers

  1. . 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.