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> Autophagy is the garbage removal system in cells. Its action in neurons, which have to last a lifetime is important:
> 
> https://medicalxpress.com/news/2020-11-insights-role-autophagy-neuron.html
> 
> "It appears that autophagy protects neurons in the brain, but for different reasons than previously assumed, as researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Charité in Berlin have now shown. When the scientists used a genetic trick to switch off autophagy-mediated cellular waste disposal, instead of detecting protein deposits, as expected, they found elevated levels of the endoplasmic reticulum, a system composed of membrane sacs which acts, among other functions, as a calcium store. This leads to elevated neurotransmitter release and, ultimately, to fatal neuronal hyperexcitability. 
> 
> "Autophagy plays a key role in the maintenance of healthy cells, one example being the degradation and recycling of damaged protein molecules or entire organelles such as defective mitochondria by means of so-called autophagosomes. This cleaning mechanism is particularly important for neurons in the brain, which serve us throughout our lives, given that autophagy clears protein aggregates, such as those occurring in neurodegenerative diseases. The neuroprotective effects of autophagy have since been confirmed by numerous experiments in model organisms.
> 
> ***
> 
> "Using a genetic trick, the researchers first switched off an essential autophagy gene, and then used proteomics to analyze neuronal protein levels. Proteins previously hypothesized to be primarily degraded by autophagy were not enriched in the neurons at all—although this would have been expected, if their degradation occurred via autophagy.
> 
> "'It came as a complete surprise to us," remarked Marijn Kuijpers, lead author of the study now published in Neuron. "But what surprised us even more was what we found in the neurons instead."
> 
> "Instead of the expected autophagy substrates, the researchers discovered unusually high levels of the endoplasmic reticulum in the neuronal axons. One of the functions of these membrane sacs and tubules, which occur in all cells, is to provide a large intracellular store for calcium. The regulation of calcium is in turn fundamentally important for excitatory transmission in the central nervous system: When neurons communicate with each other, calcium channels open at synapses, leading to an influx of extracellular calcium into synapses and the release of neurotransmitters (neuronal messengers) from synaptic vesicles. Calcium can then either be pumped out of the neuron or enter the endoplasmic reticulum from where it can also be re-released, as required.
> 
> ***
> 
> "'Until now, it was assumed that less autophagy meant the release of fewer transmitter molecules. We have now demonstrated the exact opposite," said postdoctoral fellow Marijn Kuijpers, commenting on the results of her study. "Too much, not too little neurotransmitter release is the problem. As a result, neurons become less plastic, and we suspect that they ultimately perish from hyperexcitability," added Charité's Professor Dietmar Schmitz, whose team contributed to the study.
> 
> "Since the study was conducted with healthy neurons from young animals, it does not preclude additional functions of autophagy under pathological conditions, in Alzheimer's disease, for example. That said, the study is of tremendous importance for our fundamental understanding of the physiology of autophagy."
> 
> Comment: Bit by bit we are coming to understand the complexity of preserving neurons for a lifetime. Only by very careful design.