Research Brief: Mutant Cells Eat Mutant SOD1

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.

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

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