Rudnick ND, Griffey CJ, Guarnieri P, Gerbino V, Wang X, Piersaint JA, Tapia JC, Rich MM, Maniatis T. Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS. Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):E8294-E8303. Epub 2017 Sep 13 PubMed.
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This study has added more complexity to the field, and suggests a new concept that should be considered for future therapeutic strategies to target autophagy in ALS. Despite initial expectations that blocking autophagy should exacerbate the severity of the diseases, the authors provide elegant data indicating that the opposite is true.
These results may reflect the fact that autophagy is deregulated in ALS, associated with an over-activation that is detrimental to motor neuron function. But also, the authors show that blocking autophagy restores some of the proteostasis defects observed in the disease, suggesting a complex crosstalk between different pathways that maintain the health of the proteome.
These results also confirm our previous observations indicating that, in the context of ALS, the autophagy and ER stress pathways are interconnected in a dynamic way, and that reducing autophagy levels may be beneficial. With this study, it is now becoming clear that the field needs to perform systematic studies to define the significance of autophagy to specific diseases one by one, since in certain contexts stimulating the pathway may be beneficial whereas in others it may be detrimental.
View all comments by Claudio HetzUniversity of Sheffield
Rudnick and colleagues have performed a very elegant study of autophagy in the mtSOD1 model of ALS, with some surprising results. Selective vulnerability of motor neurons has long been noted in patients and in animal models, but not understood. Independent of ALS, the authors examined Atg7 cKO mice, which have disrupted autophagy. They demonstrated that dependence on autophagy to clear ubiquitinated aggregates appears to be specific to the “fast” motor neurons, which are most vulnerable to ALS-neurodegeneration. Interestingly, these mice exhibited denervation of fast-twitch muscle fibres without overt cell death.
This mimics the earliest phase of human ALS, and therefore it was perhaps unsurprising that crossing these mice with mtSOD1 mice, which develop ALS, accelerated the progression of early denervation related to ALS.
Where this study really breaks new ground is the observation that, despite accelerated denervation in early disease, the double transgenic mice survived longer and displayed reduced levels of neuronal loss and neuroinflammation in the late phase of disease. The authors suggest that this is because the late phase of disease may be driven by pathological material taken up in autophagosomes by fast motor neurons.
Much speculation has occurred around the idea that misfolded protein may spread disease through a “prion-like” mechanism, and these data would be consistent with that idea. The conclusion of this study is that therapeutic strategies aimed at increasing autophagy of pathological aggregates may need to be careful not to accelerate toxicity by other pathways.
Some questions remain: this study has focused on the well-characterised mtSOD1 model of ALS and will require independent validation to demonstrate that it is applicable more broadly to non-mtSOD1 ALS. It is also interesting to speculate at what stage of human ALS a switch may occur from predominant fast motor neuron pathology to non-cell autonomous toxicity driven indirectly by dying fast motor neurons which have performed autophagy on pathological aggregates. This may be as early as onset of clinical symptoms—certainly neuroinflammation and gliosis is universally reported in human ALS.
View all comments by Johnathan Cooper-KnockMake a Comment
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