As far as I have understood from your question, the process of “garbage disposal “in neurons is defined as autophagy. I will leave aside the complex molecular pathways underlying them, but rather provide a short overview of “how, where, and why”. More details will be provided in the references. If you have some burning questions, feel free to ask in the comment and I will try to answer to the best of my knowledge.
1. What is Autophagy and Why is Important
Autophagy is a cellular process in charge of the degradation of dysfunctional organelles and protein aggregates (1). Autophagy is particularly important in neurons. We have to think that neurons are postmitotic cells. This means that they cannot divide anymore. Cell division can help when it comes to reducing cell damage burden as well as the accumulation of toxic proteins or dysfunctional organelles (2). This, however, is not the case of neurons. Thus, there must be in place, mechanisms able to support neuronal function throughout a lifetime by promoting clearance and renewal.
2. Autophagy in a Nutshell and the main mechanism of “garbage removal”
Autophagy begins with autophagosome biogenesis (3). In nonneuronal cells, autophagosome biogenesis is activated by cellular stressors such as starvation via the suppression of mTOR (mammalian target of rapamycin 1) kinase activity. The induction complex is mediated by different kinases like ULK1 (UNC-51-like kinase 1). When activated, ULK1 phosphorylates other autophagy pathway components, including Beclin1 (BECN1) a component of the nucleation complex. The nucleation complex generates PI3P (phosphatidylinositol 3- phosphate), an important component of the autophagosome membrane during biogenesis. Elongation of the autophagosome membrane is mediated by the so-called elongation complex, composed of two ubiquitin-like conjugation complexes. Since autophagy requires de novo membrane formation and elongation around cargo in the cytoplasm, a long debate has gone on regarding the source of the lipids that make up the autophagosome membrane. question. However, the ER has been repeatedly identified as crucial for autophagosome formation, both as a source of donor membrane and as a platform for initial biogenesis of the organelle. Once the contents of the autophagosome are engulfed, the isolation membrane must close by fusing with itself, yielding a double-layer membrane surrounding the contents. Around the time at which the autophagosome membrane fuses with itself, the biogenesis machinery dissociates from the fully formed autophagosome. The protein machinery necessary for membrane fusion at the extremities of the isolation membrane is not yet known. After autophagosome closure, it fuses with late endosomes or lysosomes. The following fusion to form an auto phagolysosome, the internal pH decreases, activating lysosomal enzymes that digest the engulfed cargos for eventual recycling of components.
Of note, Autophagy can act during neurodevelopment in neuronal precursors. Conditionally knocking out mTOR in GABAergic precursors increased autophagy in those cells and suppressed their proliferation, leading to a reduction in cortical interneurons. Thus, autophagy can modulate the first step in neuronal development, differentiation, or generation (4).
Now that we have an idea about how the autophagy works, we can see the main types in which this process is divided (5):
- mitophagy, the clearance of defective mitochondria. Interest in the mechanisms driving mitophagy was sparked by the discovery that two genes causal for familial forms of Parkinson’s disease (PD), those encoding PINK1 (PTEN-induced kinase 1) and Parkin, are part of a conserved mitophagy pathway. Also, the mutation in mitophagy related genes are associated with rare forms of familial amyotrophic lateral sclerosis (ALS)
- ER(endoplasmic reticulum)phagy: ER forms an extensive and dynamic network of sheets, tubules, and cisternae that extends throughout the cell, including neurons where it extends within the soma, dendrites and axons. The ER must be remodeled and renewed in neurons, especially under conditions of stress. One mechanism for turnover is ERphagy, the selective removal of ER segments by autophagy.
- Aggrephagy: this is the process through which protein aggregates are removed. Failure in these mechanisms is linked to neurodegenerative diseases.
Misfolded or damaged proteins can be cleared by the ubiquitin-proteasome system, but once misfolded proteins aggregate, these accumulations are cleared by autophagy.
3. Where it occurs within the Neuron
- Axons: axonal autophagosomes undergo bidirectional movement along microtubules in the distal axon; such movement is driven by kinesin and dynein motors that localize to neuronal autophagosomes. As an autophagosome is transported retrogradely along the axon, it likely fuses with additional, and more degradative competent, lysosomes.
- Dendrites: autophagy in dendrites has been also shown to regulate dendrites maintenance like branching and degeneration (6)
- Soma: it is yet to be clarified the existence of autophagic mechanisms starting directly in the neuronal soma
1- Dikic, I., Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19, 349–364 (2018). https://doi.org/10.1038/s41580-018-0003-4
2- Carlton, J.G., Jones, H. & Eggert, U.S. Membrane and organelle dynamics during cell division. Nat Rev Mol Cell Biol 21, 151–166 (2020). https://doi.org/10.1038/s41580-019-0208-1
3- Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 2014;20(3):460-473. doi:10.1089/ars.2013.5371
4- Autophagy in Neuronal Development and Plasticity Fleming, Angeleen et al. 2020 Trends in Neurosciences. doi: 10.1016/j.tins.2020.07.003
5- Autophagy in Neurons Andrea K.H. Stavoe and Erika L.F. Holzbaur Annual Review of Cell and Developmental Biology 2019 35:1, 477-500
6- Basal autophagy is required for promoting dendritic terminal branching in Drosophila sensory neurons
Clark SG, Graybeal LL, Bhattacharjee S, Thomas C, Bhattacharya S, et al. (2018) Basal autophagy is required for promoting dendritic terminal branching in Drosophila sensory neurons. PLOS ONE 13(11): e0206743. https://doi.org/10.1371/journal.pone.0206743