Lysosomal Digestion of Cellular Debris and Neurodegenerative Diseases, a Breakdown

Aaron Wang | 29 August 2024

Background

One hallmark of many neurodegenerative diseases, such as Parkinsons and Alzheimer’s disease, is the presence of the aggregation of abnormal proteins. With these proteins being explored in previous articles, these proteins have been scrutinized in the ongoing research to cure these diseases. However, even though they may not end up as the underlying cause of the diseases, these abnormal clusters do indeed cause harm to neighboring brain tissue.

If familiar with some degree of high school biology, unwanted cellular debris such these clusters of proteins should be cleared out by the cell’s waste management system. That said, the main and most known component of that waste management system is known to be carried out by lysosomes. However, due to the continued presence and the failure to clear these abnormal proteins, the lysosome may be something worth exploring in the context of neurodegenerative diseases.

Lysosomes

Lysosomes, part of the endomembrane system, is a membrane bound organelle that specializes in the digestion of cellular materials. Specifically, the lysosome is a vesicle that contains digestive enzymes called hydrolytic enzymes. Inside the vesicle, the environment is comparatively more acidic than its surroundings, as these enzymes primarily use the process of hydrolysis to break down organic molecules into its elements or monomers, which could be reused by the cell later on. Thanks to that digestive function, not only are lysosomes used as defense against pathogenic invaders such as bacteria and viruses, but they are also used to recycle. In some cases, which could potentially be applied to cancer research, when the cell is too badly damaged and may pose a risk to other healthy cells around it, lysosomes are able to release their digestive enzymes to digest the entire cell in a process known as apoptosis, or cell death.

ALP

The autophagy lysosomal pathway (ALP) is the main process by which lysosomes break down material. There are multiple distinct mini-pathways in this general pathway, with some being the macroautophagy, microautophagy, and chaperone assisted autophagy. However, all these pathways share the common feature of the fact that digestion always occurs in the lysosome (Finkbeiner, 2020).

Macroautophagy

Macroautophagy is one of the more common ones, with the pathway beginning with the formation of a regular vesicle that contains materials to be broken down. This vesicle, called the autophagosome, doesnt digest but merely contains the material. Later on, through fusion, the lysosome assimilates the autophagosome and proceeds to digest the contents inside.

Microautophagy

Microautophagy function in a similar way, except that there is no need for the formation of an autophagosome to temporarily store the cellular materials to be digested. As a result, materials that are slated for digestion are directly assimilated by the lysosome in a process similar to pinocytosis. Proteins, such as the hsc70 protein family, may help transport these misfolded proteins (Finkbeiner, 2020), and this pathway could potentially play a role in the reason why beta-amyloids tend to build up in patients with neurodegenerative diseases.

Chaperone assisted autophagy

When proteins are misfolded and therefore dysfunctional, those proteins must be eliminated in order to prevent buildup. In a routine method, lysosomes can digest these proteins using the chaperone assisted autophagy pathway. Chaperones, which are proteins that assist in protein folding and transportation, bind to the misfolded proteins and transport them directly to the lysosome for destruction. Although this pathway specifically targets proteins, the process of transportation reduces its efficiency in clearing out abnormal proteins. However, the activation of this pathway has been observed to help with the clearance of protein debris (Finkbeiner, 2020; Massey 2006).

ALP and neurodegeneration

The ALP plays a massive role in the degradation of materials that pose a threat to the health of a cell, and in the context of a buildup of toxic proteins in neurodegeneration, the ALP becomes a more relevant player in the field. Mutations in genes that govern the process of the pathways have been identified as possible factor of correlation in Alzheimers (Kegel, 2020). Specifically, the inability of the pathway to keep up with clearing beta-amyloid proteins, especially with the overproduction of these toxic proteins, contributes to the onset of diseases such as Alzheimer’s.

However, it is observed that there are some differences in the way that neurons, which are post-mitotic cells, use lysosomes. Because of the neuron’s special structure, in regards to its long extensions, autophagosomes were observed to be created in the long arms of the neurons (axon terminals) and transported to the main cell body where the lysosomes digest the contents held inside (Maday and Holzbaur 2014). As a result, it can be postulated that, because axon terminals and dendrites can end up to be extremely long, the movement of autophagosomes may be prolonged and therefore extend the length of the process of digestion. In addition to that, any mutations in the ALP pathway may compound the issue. Therefore, mutations in the ALP may prove more detrimental than normal due to the vulnerability of the neuron in context of the ALP.

To corroborate this, mutations in ALP were observed, in multiple studies, to be strongly correlated and linked to neurodegenerative diseases. In mouse models, ATG7, a gene that regulates autophagy, was killed and the results were observed. Motor neurons, because it could no longer process the buildup of waste, were quickly affected, and abnormal behavior was recorded.

Conversely, the stimulation of the pathway could prove to assist in the treatment of symptoms of neurodegenerative diseases like Alzheimer’s disease. However, this field is extremely complicated and the targeting of the ALP could result in unintended side effects. There have been no human trials on this type of treatment as well as uncertainty about accidentally inhibiting other important functions of other organelles. There has been evidence that even suggested that targeting the ALP could result in the propagation of cancer cells (Shintani, 2004), as well as the overaccumulation of autophagosomes.

Works Cited

Finkbeiner S. The Autophagy Lysosomal Pathway and Neurodegeneration. Cold Spring Harb Perspect Biol. 2020 Mar 2;12(3):a033993. doi: 10.1101/cshperspect.a033993. PMID: 30936119; PMCID: PMC6773515.

Kegel KB, Kim M, Sapp E, McIntyre C, Castaño JG, Aronin N, DiFiglia M. 2000. Huntingtin expression stimulates endosomal–lysosomal activity, endosome tubulation, and autophagy. J Neurosci 20: 7268–7278. 10.1523/jneurosci.20-19-07268.2000

Maday S, Holzbaur EL. 2014. Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. Dev Cell 30: 71–85. 10.1016/j.devcel.2014.06.001 

Massey, Ashish C et al. “Chaperone-mediated autophagy in aging and disease.” Current topics in developmental biology vol. 73 (2006): 205-35. doi:10.1016/S0070-2153(05)73007-6

Shintani T, Klionsky DJ. 2004. Autophagy in health and disease: A double-edged sword. Science 306: 990–995. 10.1126/science.1099993