This paper from Saxena et al. is a very interesting, even outstanding paper. Despite that ER stress has been conceptually linked before to ALS development, the experiments performed here offer a novel view on the chronology of facts before denervation and symptom development in relevant experimental models. It should be useful also for other diseases, where ER stress has been also involved.

Several findings are really surprising: 1) the clear division between resistant motor neurons (RES) and vulnerable ones (VUL); 2) the predictability on development of the disease that the pathogenic scheme described by authors allows; 3) the dissociation between ubiquitination—often considered a pathological hallmark for this disease and other neurodegenerative diseases—and real axonal pathology; 4) the very early changes at a cellular level (as early as postnatal 5 in some markers) that preclude pathological changes; 5) the presence of novel markers of the disease at an immunological level (such as ATF3, PERK, and similar); 6) the distinctive patterns of expression between RES and VUL...  Read more

This paper from Saxena et al. is a very interesting, even outstanding paper. Despite that ER stress has been conceptually linked before to ALS development, the experiments performed here offer a novel view on the chronology of facts before denervation and symptom development in relevant experimental models. It should be useful also for other diseases, where ER stress has been also involved.

Several findings are really surprising: 1) the clear division between resistant motor neurons (RES) and vulnerable ones (VUL); 2) the predictability on development of the disease that the pathogenic scheme described by authors allows; 3) the dissociation between ubiquitination—often considered a pathological hallmark for this disease and other neurodegenerative diseases—and real axonal pathology; 4) the very early changes at a cellular level (as early as postnatal 5 in some markers) that preclude pathological changes; 5) the presence of novel markers of the disease at an immunological level (such as ATF3, PERK, and similar); 6) the distinctive patterns of expression between RES and VUL neurons; 7) the interplay between growth factor treatment (CTNF) and rescue in ER stress terms; and 8) the positive effect of salubrinal in ALS development and the negative effects of crushing schemes

The findings fit quite well with some of the "usual suspects" theories of ALS, such as the involvement of mitochondria and glia. Mitochondrial impairment (due to unfolded SOD or to other events) would lead to lower ATP levels or to Ca homeostasis dysregulation, which would affect the ER, increasing the unfolded protein response (UPR). Additionally, and pertinent to our case since we linked ER stress to oxidative stress, ER folding capacities are strongly influenced by oxidative milieu and the findings reported here (including participation of hypoxia and NRf2 dependent pathways) agree with the potentially increased oxidative stress in VUL neurons. Most interestingly, many data (as recently reviewed by Cleveland et al. in the last Cell volume—see Lagier-Tourenne et al., 2009) point out the importance of RNA processing in ALS. The hypothetical interplay between alterations in RNA splicing and ER stress in VUL neurons is in agreement with the high structural and energetical requirements of those cells. It seems that long axons and the structural and functional needs that those "near to pathology" cells (VUL motor neurons) exhibit, make them extremely prone to pathology.

It is also somewhat surprising that ER stress, which may be considered a logical and physiological consequence of UPR, is followed by cellular demise. It would be also be very interesting, as apoptosis seems not involved, to characterize the distal events of ER stress; i.e., what is the link between ER stress and denervation. This is because although the authors define that salubrinal treatment is useful at preclinical stages, it seems that its efficiency would be much lower at a clinical stage.

It would be nice to confirm these results in human samples. Though it could be difficult to find VUL and RES motor neurons in samples from human disease specimens, but this would also be useful to extend those findings to the more common form of the disease (sporadic ALS, by far, is commoner than the familial form). Further experiments would have to prove, by in vitro transfection with some of the factors described in the papers, that RESistance to disease is acquired by VULnerable neurons (or vice versa, by using RNAi or similar techniques).

View all comments by Manuel Portero

This paper from Eckhart Mandelkow's group seems directly related to the question at hand:

Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J Cell Biol. 1998 Nov 2;143(3):777-94. Abstract

View all comments by P.F. Jennings