The Cases of Diseased Organelles #2: Lysosomes

You are cells. Cells are the basic units of structure and function in all living organisms. Organelles inside cells, likened to “tiny organs,” help cells function by performing jobs they are responsible for completing. When these organelles become diseased, problems arise. Welcome to The Cases of Diseased Organelles #2: Lysosomes.

Vesicles are membrane-enclosed sacs that aid in the transportation of materials from one location to another, whether intracellular or intercellular. The word “vesicle” is a collective term for distinct types of organelles categorized under it. Of the many prominent organelles in a cell, vesicles are often overlooked; however, they are one of the most indispensable parts of the cell. Lysosomes are vesicles that serve as the rubbish depository of the cell. Their appearance is similar to that of a vacuole, another vesicle. Containing within their structure hydrolytic enzymes that have digestive abilities, lysosomes have the capability to destroy disease-causing organisms. It is paramount that lysosomes operate well as the smallest of errors could pave the way for diseases to enter the cell or for cellular waste to remain intracellular.

Lysosomal storage diseases (LSDs) are common consequences caused by defects in lysosomes. Fabry disease and Gaucher disease are among the fifty genetic abnormalities categorized as LSDs. Most LSDs manifest during one’s early years. The dysfunction behind an LSD is “characterized by the accumulation of substrates in excess in various organs' cells due to the defective functioning of lysosomes” (Rajkumar and Dumpa). Since LSDs are passed down from generation to generation, the manifestation of the disease’s characteristics is the direct result of inheriting a gene from one or both parents (“Pediatric LSDs”). Lysosomes serve as the digestive units within a cell; hence, the body’s metabolism is hindered when the lysosomes do not function correctly. This further causes material build-up within lysosomes; consequently, enzymes become deficient because the capacity is now abnormal. Since enzymes function by binding to substrates, a deficiency in enzymes corresponds to an excess accumulation of substrates. The accumulation of enzymes normally collects in organs. With the loss of important enzymes and the aggregation of substrates, without enzymes, there is cellular dysfunction, which presents a high chance of fatality. Individuals with Fabry disease may also develop long-term kidney, heart, and skin issues. In cases of Fabry disease, there is a mutation in the GLA gene, the one responsible for producing alpha-galactosidase A enzymes. These enzymes are what lysosomes use to break down globotriaosylceramide, which consists of a fatty substance attached to three sugars (“GLA Gene”). In the event of a mutation, the protein-coding function for the GLA gene is altered; consequently, the enzyme is not properly created for lysosomal use. Additionally, the GLA gene is sex-linked; therefore, one defective copy is sufficient for males to inherit the disease completely (“What is Fabry’s”). On the other hand, the gene works differently for females. Females have less severe symptoms of Fabry disease because they inherit one defective copy. It is uncommon for a female to be a true carrier since they inherit one copy of the gene but display no indications of the disease at all. Even so, the gene is still passed on to the genotype of future offspring.

Gaucher disease, on the other hand, is caused by a mutation in the glucocerebrosidase (GBA1) gene. The disease is the most common cause of lysosomal storage diseases, “occurring in 1 in 40000 to 1 in 60000 in the general population” (Rajkumar and Dumpa). According to William L. Stone, a researcher at East Tennessee State University, and his colleagues, GBA1 is “an enzyme that cleaves beta-glucosidic linkage of glucocerebroside lipids.” When the function of the housekeeping enzyme is altered, large sugar molecules cannot be broken down into simple fat molecules (“GBA Gene”). A mutation in the gene reduces or completely eliminates the enzyme beta-glucocerebrosidase in a cell, which can alter the instructions given in a cell and create a counterproductive lysosome. Gaucher disease results as a “toxic accumulation inborn error of metabolism due to the accumulation of glucocerebroside lipids” (Stone et. al). The disease manifests in different aspects. For example, a patient with Gaucher disease may have an enlarged liver and spleen. An enlarged liver and spleen are usually signs pointing to serious health issues that may be life-threatening. Extra pressure put on the spleen affects its overall blood flow. Hematologically, one can encounter thrombocytopenia, anemia, and leukopenia (Stone et. al). Thrombocytopenia is a disease that results in a low platelet count. Anemia is a common condition that affects the amount of oxygen in blood because of the lack of red blood cells. Leukopenia describes the decrease in blood leukocytes, which decreases the body’s ability to fight off disease. Low bone density, pathological fractures, and osteonecrosis may also be skeletal repercussions of Gaucher’s disease (Stone et. al). Low bone density causes overall body weakness and a tendency for injury, while osteonecrosis is the death of bone cells. There are three types of Gaucher’s disease, and some types may have neurological consequences, which is why it may be fatal in the prenatal stage or within the first few years of life. Those with the disease who survive childhood may have a shorter life expectancy than healthy individuals.

Common treatment options for LSDs include transplantations through umbilical cord blood stem cells to restore missing enzymes in development, transplantations through bone marrow to slow disease advancement, or an intravenous (IV) enzyme replacement (“Pediatric LSDs”). There is no cure for the aforementioned diseases yet; however, research shows promise for advancement.

While lysosomal diseases are difficult to treat, the current body of research looks to expand the quality and expectancy of life. Understanding the inner functions of the organelles and the causes of diseases is one step forward toward the possibility of discovering more effective treatments in the future.

References

“GLA Gene” Medline Plus, 1 Mar. 2007. medlineplus.gov/genetics/gene/gla/. Accessed 22 Nov. 2022.

“Pediatric Lysosomal Storage Diseases.” Children’s National. 2022. childrensnational.org/visit/conditions-and-treatments/genetic-disorders-and-birth-defects/lysosomal-storage-disorders. Accessed 22 Nov. 2022.

Rajkumar, Venkatraman and Vikramaditya Dumpa. Lysosomal Storage Disease. Stat Pearls, 25 July 2022. National Library of Medicine. www.ncbi.nlm.nih.gov/books/NBK563270/#:~:text=Lysosomal%20storage%20diseases%20(LSDs)%20are,to%20great%20morbidity%20and%20mortality. Accessed 22 Nov. 2022.

Stone, William, Hajira Basit, and Samip R. Master. Gaucher Disease. Stat Pearls, 7 June 2022. National Library of Medicine. www.ncbi.nlm.nih.gov/books/NBK448080/#:~:text=Gaucher%20disease%20is%20a%20%E2%80%9Ctoxic,physiological%20turnover%20of%20cell%20constituents. Accessed 22 Nov. 2022.

“What is Fabry’s Disease?” UCLA Health, 2022. www.uclahealth.org/programs/core-kidney/conditions-treated/fabrys-disease/what-fabrys-disease#:~:text=The%20enzyme%20associated%20with%20Fabry%27s,leading%20to%20multiple%20organ%20dysfunction. Accessed 22 Nov. 2022.