Lysosomal Storage Disease


Lysosomes are a membrane-bound organelle found in many animal cells. They are spherical vesicles containing hydrolases that break down many biomolecules. The pH of the lysosome in the range of 4.5 to 5.0 is optimal for the enzyme involved in the hydrolysis. Lysosomes perform waste treatment functions by digesting unused or unused materials from the cytoplasm inside and outside the cell. Among them, substances from outside the cell are absorbed by endocytosis, while substances from inside the cell are digested by autophagy.
Lysosomes need to break down unwanted substances into raw materials, which are then used by cells to synthesize new substances. In this process, lysosomes function is realized by decompose these unwanted substances by enzymatic reactions. A lysosomal disorder is usually triggered when a particular enzyme is present in too small amounts or is completely absent. When this happens, the substance will accumulate in the cells. In other words, when the lysosome does not function properly, excess product for decomposition and recycling will remain in the cells.
Lysosomes are known to contain more than 60 different enzymes and have more than 50 membrane proteins. The synthesis of these enzymes is controlled by nuclear genes. When these genes are mutated, they will result in more than 30 different human genetic diseases, collectively referred to as lysosomal storage diseases. They are caused by the inability to decompose unwanted substances, which in turn leads to the accumulation of specific substrates. These genetic defects are closely linked to several neurodegenerative diseases, cancer, cardiovascular disease and aging-related diseases.
Type of Lysosomal Storage Disease
A genetic defect involved in lysosomes, called a lysosomal storage disease (LSD) mutation, is a congenital metabolic error caused by a dysfunction of an enzyme. The main reason is the lack of acid hydrolase. Other conditions are due to defects in the lysosomal membrane protein that result in the inability of the enzyme to transport. The initial effect of this disease is the accumulation of specific macromolecules or monomeric compounds within the endosome-autophagy-lysosomal system. This leads to abnormal signaling pathways, calcium homeostasis, lipid biosynthesis and degradation, and intracellular trafficking, ultimately leading to pathogenic diseases. The organs most affected are the brain, internal organs, bones and cartilage.

Figure 1. Examples of cellular pathogenesis in lysosomal storage diseases.

Some lysosomal storage diseases and some characteristic symptoms and symptoms are as follows:
Aspartylglucosaminuria: The disease is caused by an enzyme deficiency called aspartyl glucosaminidase. This enzyme plays an important role in the human body because it helps break down certain sugars that are linked to specific proteins, such as glycoproteins. These proteins are most abundant in the surface of body tissues and major organs such as the liver, spleen, thyroid and nerves. When the glycoprotein is not decomposed, the aspartyl glucosaminase is accumulated with other substances in the lysosome. This accumulation can cause progressive damage to tissues and organs.
Cystine disease: Cystine disease is a lysosomal storage disease characterized by abnormal accumulation of cystine. Cystine is a lysosomal membrane-specific transporter of cystine. Like all amino acids, the intracellular metabolism of cystine requires its transport across cell membranes. After the endocytic protein degrades into cystine in the lysosome, it is usually transported into the cytosol. However, if the CTNS gene encoding cystine is mutated, cystine will accumulate in the lysosome. Since cystine is highly insoluble, when its concentration in tissue lysosomes is increased, its solubility is easily exceeded and a crystalline precipitate is formed in almost all organs and tissues.
Fabry disease: Fabry disease is also known as α-galactosidase A deficiency. Fabry disease is caused by a mutation in the GLA gene. This gene regulates the production of α-galactosidase A. Alpha-galactosidase A usually breaks down a fatty substance called globotriaosylceramide. Mutation of the GLA gene alters the structure and function of the enzyme, inhibiting its efficient decomposition of the substance. As a result, spherical triacylceramide accumulates in cells throughout the body, particularly blood vessels and kidneys in the skin, cells in the heart and nervous system. The gradual accumulation of this substance destroys the cells and causes various signs and symptoms of Fabry disease.
Gaucher disease type I, II and III: Gaucher disease is the most common lysosomal storage disease. The researchers identified three different types of gaucher disease based on the presence and extent of neurological complications in the absence. Studies found mutations in the GBA gene cause gaucher disease. The GBA gene provides instructions for the preparation of an enzyme called beta-glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside into sugar (glucose) and a simpler fat molecule (ceramide). Mutation of the GBA gene greatly reduces or eliminates the activity of β-glucocerebrosidase. Without enough of this enzyme, glucocerebroside and related substances can reach toxic levels in cells. Abnormal accumulation and storage of these substances damage tissues and organs and cause the characteristics of gaucher disease.
Glycogen storage disease II (Pompe disease): Pompe disease is caused by mutation of the GAA gene. The gaa gene provides instructions for the production of an enzyme called acid-glucosidase (also known as acid maltase). This enzyme is active in lysosomes, which usually break down glycogen into glucose. Mutations in the gaa gene inhibit the acid-glucosidase from breaking down the glycogen, allowing the sugar to accumulate in lysosomes to toxic levels. This accumulation can damage organs and tissues throughout the body, especially muscles, leading to symptoms and signs of Pompe disease.
GM2-ganglioside type I (Tay Sachs disease): Mutations in the HEXA gene cause Tay-Sachs disease. The HEXA gene provides instructions for the synthesis of an enzyme called β-hexose amino A. It plays a vital role in the brain and spinal cord. The enzyme is located in the lysosome and can decompose toxic substances. In lysosomes, β-hexosaminidase A helps break down fatty substances called GM2 gangliosides. Mutations in the HEXA gene disrupt the activity of β-hexosaminidase A, thereby preventing the enzyme from breaking down GM2 gangliosides. As a result, this substance accumulates to toxic levels, particularly in the brain and spinal cord in neurons. Progressive damage caused by accumulation of GM2 gangliosides leads to destruction of these neurons, which leads to symptoms and signs of Tay-Sachs disease Tay-Sachs disease.
Mucolipidosis II alpha / beta: Mutations in the GNPTAB gene result in mucolipidosis II alpha / beta. This gene directs the synthesis of GlcNAc-1-phosphotransferase. This enzyme helps transport some newly manufactured enzymes into lysosomes. GlcNAc-1-phosphotransferase is involved in the process of attaching a molecule called mannose-6-phosphate (M6P) to a specific digestive enzyme. The process is to place markers on the enzyme so that they reach the desired location in the cell. M6P acts as a label indicating that the digestive enzyme should be transported to the lysosome. Mutations in the GNPTAB gene that cause mucolipidosis II alpha / beta prevent the production of any functional GlcNAc-1-phosphotransferase. Without this enzyme, digestive enzymes cannot be labeled with M6P and transported into lysosomes. Instead, they eventually enter the cell and increase digestive activity. The lack of digestive enzymes in the lysosome leads to the accumulation of macromolecules there. The signs and symptoms of mucolipidosis II alpha / beta are most likely due to the lack of digestive enzymes in the lysosome and the extracellular effects of these enzymes.

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