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Jamila Jul 30, 2020
How Is Neuronal Garbage Processed?
Image credit: Arnold et al. 2018 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789552/)
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How is neuronal garbage processed in humans?
Research on neuronal garbage processing has mostly been conducted in C. elegans and some murine cells. Many aspects of the neuronal garbage removal process are yet to be elucidated. In Melentijevic’s study, C. elegans neurons expelled a large vesicle which was later named as an exopher. The exopher may sound like an exosome but it certainly is not. On average the exophers were 4uM, thus exosomes are significantly smaller than exophers. Exophers are able to remove protein aggregates, lysosomes, and even mitochondria.
There are many questions that still need to be answered
- What is the specific mechanism in which the trash is recognized?
- What is the exact mechanism of ejection from the cell?
- Where does the trash go and how is it degraded in mice and human cells?
Plaque-like structures are able to form from exophers carrying amyloid-beta. This information can provide insight into neurological disease progression that can be characterised with amyloid plaque, ghost tangles, and Lewy body formation.
[1]Melentijevic, Ilija, et al. "C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress." Nature, 542.7641, 2017, pp. 367-371.
[2]Fu, Hualin, et al. "Metabolic wastes are removed by excretosomes, nanotubes and exophers in mouse HT22 cells through an autophagic vesicle clustering mechanism." bioRxiv, 2019, pp. 699405.
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Removal of Cellular Trash
Essentially all neurodegenerative diseases are associated with the mis-accumulation of cellular waste products. Of these, misfolded or hyperphosphorylated proteins are among the most difficult for the brain to dispose of. For example, tau and β-amyloid can accumulate as stable aggregates that are neurotoxic in conditions such as Alzheimer’s disease (1). Intracellular proteasomal degradation and autophagy are considered the principal means for removing proteins in the central nervous system, and the dysfunction of each has been causally associated with neurodegeneration (2). Yet many cytosolic proteins are released into the interstitial space in the brain, suggesting that extracellular disposal routes may also eliminate waste (3).
Throughout the body’s tissues, bulk flow of the fluid between cells, into the blood or lymph, plays an important role in the removal of potentially toxic metabolic by-products. Lymphatic vessels, which run in parallel with the blood vascular system, are the principal means by which tissues eliminate excess fluid and proteins. Although the density of lymph vessels generally correlates with tissue metabolic rate (4), the brain and spinal cord are curiously devoid of such a lymphatic tree. This is puzzling because of the high metabolic activity of neurons predicts the need for rapid elimination of their metabolic byproducts. It was long thought that movement of the cerebrospinal fluid (CSF), which is produced in the choroid plexus of the brain and flows through its ventricles and basal cisterns, constitutes a “sink” for waste products to diffuse from the brain, for eventual clearance to the general circulation. However, the large tissue distances in most of the brain prevent diffusion and bulk flow from making this process efficient. Albumin, for instance, would require more than 100 hours to diffuse through 1 cm of brain tissue (5).
To keep themselves neat, tidy and above all healthy, cells rely on a variety of recycling and trash removal systems. If it weren't for these systems, cells could look like microscopic junkyards - and worse, they might not function properly.[6]
One of the cell's trash processors is called the proteasome. It breaks down proteins, the building blocks, and mini-machines that make up many cell parts. The barrel-shaped proteasome disassembles damaged or unwanted proteins, breaking them into bits that the cell can re-use to make new proteins.[7] In this way, the proteasome is just as much a recycling plant as it is a garbage disposal.
Proteins aren't the only type of cellular waste. Cells also have to recycle compartments called organelles when they become old and worn out.[8] For this task, they rely on an organelle called the lysosome, which works like a cellular stomach. Containing acid and several types of digestive enzymes, lysosomes digest unwanted organelles in a process termed autophagy.[9]
While cells mainly use proteasomes and lysosomes, they have a couple of other options for trash disposal. Sometimes they simply hang onto their trash, performing the cellular equivalent of sweeping it under the rug. Scientists propose that the cell may pile all the unwanted proteins together in a glob called an aggregate to keep them from gumming up normal cellular machinery [10]. If the garbage can't be digested by lysosomes, the cell can sometimes spit it out in a process called exocytosis. Once outside the cell, the trash may encounter enzymes that can take it apart, or it may simply form a garbage heap called a plaque. Unfortunately, these plaques outside the cell may be harmful, too.[11]
Further study of the many ways cells take out the trash could lead to new approaches for keeping them healthy and preventing or treating disease.
References
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Autophagy as mechanism of garbage disposal in Neurons
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
References:
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
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Neuronal Junk May Be Tagged
Only aggregated proteins are concentrated in c. elegan exophers, this means that the neuronal garbage is distinguished from normal/healthy proteins. How is the neuronal garbage distinguished from the normal proteins then? Researchers hypothesise that specific cellular proteins may detect the neuronal junk and then guide the neuronal junk to the site where the exopher will form in c. elegans. [1]
In murine cells (HT22 cells), the cell cytoplasm and exopher contain proteins with toxic modifications and proteins marked with LC3 or ubiquitin. This suggests that junk may be marked for degradation, as autophagic vesicle clustering and fusion occurs after. [2]
Reference
1.Melentijevic, Ilija, et al. "C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress." Nature, 542.7641, 2017, pp. 367-371.
2.Fu, Hualin, et al. "Metabolic wastes are removed by excretosomes, nanotubes and exophers in mouse HT22 cells through an autophagic vesicle clustering mechanism." bioRxiv, 2019, pp. 699405.