Read with caution!
This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.
Some thoughts on autophagy:
Authophagy is an intracellular recycling process by which components of a cell are sequestered and delivered to lysosomes for degradation. Its potential role in a variety of different diseases, from cancer to infectious disease, has gotten a lot of attention in the past few years. The role of autophagy in neurodegenerative disease is complex, as it is one of the three cell death pathways (the others are apoptosis and necrosis) and under some circumstances, may promote neuronal death. However, evidence seems to be emerging for the neuroprotective role played by autophagy in cleaning up defective proteins.
Since autophagy’s maintenance functions are compromised by aging, this provides one theory as to why genetic neurodegenerative diseases typically develop late in life even though defective proteins are present all along.
Obviously tinkering with a cell death pathway is tricky business, but given the wide range of potential applications it seems like a lot of effort will be put into exploring the potentially therapeutic effects of selectively promoting autophagy. In the meantime, exercise seems to promote autophagy, and there’s evidence that autophagy is a key part of how we benefit from exercise.
“Autophagy in neurodegenerative disease: friend, foe, or turncoat?” Nixon, Trends in Neuroscience (2006)
[O]bservations that inhibitors of autophagy accelerate starvation-induced apoptosis establish that autophagy precludes apoptosis in this way. Activated capsase-3 has been found within neurons in mouse models of Alzheimer’s disease, but it is mainly confined to autophagosomes, consistent with a role in scavenging pro-apoptotic factors. Macroautophagy is particularly crucial in the aging nervous system for protecting cells from cumulative oxidative damage to proteins and membranes, from synthesis of defective proteins, and from other genetic and environmental insults. Survival of a cell in the face of mounding age-related and disease-related insults depends on how well this burden of damaged constituents can be eliminated. Given the increased need for autophagy in the aging brain, it is significant that lysosome function and efficiency of autophagy decline during aging, explaining in part the increased risk that aging confers for neurodegenerative disorders that involve accumulation of abnormal proteins. (530)
Autophagy dysfunction is emerging as a theme in neurodegenerative diseases in which mis-aggregated proteins accumulate, including Alzheimer’s disease, Parkinson’s disease and the polyglutamine expansion diseases. It has long been puzzling why protein aggregation and neurotoxicity develop so late in life, even in familial forms of disease where the mutant protein is present throughout life. It now seems likely that declining efficiency of protein turnover is partly to blame. Both macroautophagy and CMA [chaperone-mediated autophagy] slow considerably during normal aging, contributing directly to declines in tissue performance. Genetic ablation of autophage in mice has been recently shown to induce neurodegeneration and accumulations of ubiquitinated proteins. Moreover…some gene mutations that cause neurodegenerative disease directly impair the proteolytic systems responsible for degrading the mutant protein. (532)
“Loss of autophagy in the central nervous system causes neurodegeneration in mice,” Komatsu et al., Nature (2006)
Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioral defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in the autophagy-defiicient neurons as inclusion bodies, which increased in size and number with aging. There way, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.
“Autophagy: basic principles and relevance to disease,” Kundu and Thompson, Annual Review of Pathology: Mechanisms of Disease (2007)
The role of autophagy as an adaptive, protective response in these proteopathies is supported by extensive evidence that these disease-related proteins (and protein aggregates) are degraded by autophagy. Significantly, with respect to the prospect of therapeutic intervention, genetic or chemical manipulation of autophagy can modify the disease phenotypes in animal models of disease.
“Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis,” He et al., Nature (2012)
The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control2. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism3. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance4, 5, 6. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2–beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
“Exercise as Housecleaning for the Body,” Reynolds, New York Times (Feb 1, 2012)