Autophagy’s Paradoxical Role in ALS

Tue, 11/14/2017 - 10:21

By Yoskaly Lazo-Fernandez, PhD

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurological disease that affects the motor neuron system and thus voluntary control of muscle movement. This disease belongs to a broader group of disorders known as motor neuron diseases, characterized by progressive degeneration and death of motor neurons. There are two types of motor neurons, including upper- and lower-motor neurons, based on the position of their somas within the CNS. Upper motor neuron somas are located in the motor cortex and their axons descend to the spinal cord where they activate the lower motor neurons. Lower motor neurons have somas within the spinal cord and extend their axons peripherally to innervate skeletal muscles. In ALS patients, both upper and lower motor neurons degenerate and die, causing muscular atrophy and eventually, paralysis. As disease progresses, the diaphragm is also affected, thus ultimately the majority of ALS patients die from respiratory failure within 5 years after the first symptoms1.

Currently, there is limited understanding of the etiology of ALS, and there is no cure or effective treatment for this disease, which occurs in approximately 5 per 100, 000 individuals in the United States1,2. In general, it is recognized that ALS results from the adverse interaction of numerous environmental and genetic factors. In recent years it’s been recognized that factors that affect autophagy have particular prominence in the etiology of ALS. In fact, 12 out of the 25 genes that are currently known to cause familial ALS are implicated in protein homeostasis1. In addition, an important selective autophagy receptor, p62, is commonly present in the protein aggregates that are a pathological signature in ALS affected neurons7,8.

Several studies in transgenic models support that dysfunctional autophagy contributes to the development of ALS. Activation of autophagy had beneficial effects on ALS disease progression in some cases3,5, but negative in others4,5. A better understanding of the molecular mechanisms by which altered autophagy influences the development of ALS is essential for our ability to develop new therapies for this disease.


ATG7 participates in ubiquitin like conjugation complexes that are critical for the elongation of the phagophore and formation of the mature autophagosome. The ATG7/ATG3 complex, together with ATG4, participate in the lipidation of LC3 and association of LC3II to the phagophore membrane.

A recent article by Rudnick et al. provides new light on the complicated relationship between autophagy and ALS8. This group studied a transgenic mouse model expressing a mutant form of superoxide dismutase (SOD1), a genotype that leads to familial ALS in human patients, and a transgenic mouse with Atg7 deletion in motor neurons. ATG7 is an E1-like enzyme required for autophagosome biogenesis and absence of ATG7 is known to inhibit autophagy.

The study8 showed that inhibition of autophagy in the motor neurons of ALS model mice accelerated the onset of the disease, suggesting that stimulation of autophagy may play a beneficial role early in ALS progression. A particular subset of fast motor neurons was more sensitive to impaired autophagy. Fast motor neurons, which stimulate larger muscle groups, are the first cells affected in ALS. Surprisingly, inhibition of autophagy alleviated the pathology of ALS late in the progression of the disease, which suggests that pharmacological activation of autophagy could be damaging to ALS patients once the disease has surpassed the initial stage of focalized muscular tremors. The cause of these opposing effects of autophagy on ALS is still not completely understood. The results from this and other studies suggest that autophagy function is important to protect fast motor neurons from the damage caused by p62 containing protein aggregates, particularly in their presynaptic terminals. However, autophagy has also been implicated in exosome secretion9, as a mechanism that can spread toxic proteins and cause neurodegeneration. This could be a process by which misfolded protein aggregates spread to other cell types in ALS and cause cellular damage beyond fast motor neurons.

In summary, the development of autophagy-stimulating drugs to promote the degradation of protein aggregates in ALS patients could be an effective approach to treat ALS and other neurodegenerative diseases. However, recent scientific results indicate that this strategy might only be effective very early in the ALS progression. Autophagy stimulation at later stages could accelerate the progression of the disease. More research is needed to understand the mechanisms by which autophagy influences the pathophysiology of ALS and other neurodegenerative disorders.

Learn more about autophagy in neurodegeneration

Yoskaly FernandezYoskaly Lazo Fernandez, PhD
Emory University, Department of Medicine/Renal Division
Dr. Lazo-Fernandez is interested in understanding the dietary factors that contribute to the development of hypertension and other chronic diseases.


  1. Brown & Al-Chalabi. Amyotrophic Lateral Sclerosis. The New England Journal of Medicine 377, 162–172 (2017). DOI: 10.1056/NEJMra1603471.
  2. Marin et al. Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis. International Journal of Epidemiology dyw061 (2016). DOI: 10.1093/ije/dyw061
  3. Mizushima, Yoshimori & Ohsumi. The Role of Atg Proteins in Autophagosome Formation. Cell and Developmental Biology 27, 107–132 (2011). DOI: 10.1146/annurev-cellbio-092910-154005.
  4. Mizuno et al. Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. Journal of the Neurological Sciences 249, 13–18 (2006). DOI: 10.1016/j.jns.2006.05.060
  5. Castillo et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9, 1308–1320 (2013). DOI: 10.4161/auto.25188.
  6. Li et al. Trehalose decreases mutant SOD1 expression and alleviates motor deficiency in early but not end-stage amyotrophic lateral sclerosis in a SOD1-G93A mouse model. Neuroscience 298, 12–25 (2015). DOI: 10.1016/j.neuroscience.2015.03.061.
  7. Zhang et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412–25 (2011). DOI: 10.4161/auto.7.4.14541.
  8. Rudnick et al. Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS. Proceedings of the National Academy of Sciences 114, E8294–E8303 (2017). DOI: 10.1073/pnas.1704294114.
  9. Baixauli, López-Otín & Mittelbrunn. Exosomes and Autophagy: Coordinated Mechanisms for the Maintenance of Cellular Fitness. Frontiers in Immunology 5, 403 (2014). DOI: 10.3389/fimmu.2014.00403.

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