Gaucher’s Disease Type 1

Author: John Hanna

Gaucher’s Disease Type 1 is a rare disease that is characterized by an abnormal buildup of
a cellular component called glucosylceramide. Particularly, glucosylceramide can be found in the cell membrane, which is the bilayer that is responsible for protecting and organizing the cell, as well as regulating many important processes such as material exchange with the surroundings. Glucosylceramide itself plays an important role in cell signaling, in which cells coordinate with each other to undergo various functions within the body. Though, the amount of glucosylceramide in cells is regulated by a protein (enzyme) called glucocerebrosidase (GCase). Enzymes are biological catalysts that promote important chemical reactions in the body, and GCase is the one responsible for breaking down glucosylceramide when necessary. In the case of Gaucher’s Disease, this particular enzyme is either absent or non-functional, which in turn results in the accumulation of the component on which it acts (glucosylceramide) and therefore manifestation of Gaucher’s Disease.

From here we must ask, how does GCase become non-functional? And how does the accumulation of glucosylceramide lead to Gaucher’s? When discussing GCase abnormalities, we must first consider what gave rise to GCase. In almost all living organisms, DNA is the hereditary material that is passed through generations and carries the instructions for processes such as growth, reproduction, and all functioning of life. These instructions produce proteins, which are the cellular players that carry out the above processes and the various functions of the body. However, these instructions are sometimes flawed (mutated), which can lead to certain abnormalities. In the case of Gaucher’s Disease, the instructions (GBA1 gene) that give rise to GCase are the ones that are mutated, which results in non-functional GCase that is not able to breakdown glucosylceramide, leading to its buildup.

Now that we established how glucosylceramide accumulates, it is important to ask where it does so. Immune cells called macrophages are rich in small organelles called lysosomes. These lysosomes contain many enzymes that breakdown toxins, and one of the enzymes happens to be GCase. Therefore, buildup of glucosylceramide occurs mainly in macrophages, which are transformed into unique spiral-shaped Gaucher cells not present in any other disease; making them important markers for identification of Gaucher’s Disease.

Over the past several years, research has been done on Gaucher’s in order to identify other factors that may influence its manifestation. In 2016, scientists focused on a previously unrecognized factor that was thought to associate with Gaucher’s disease called PGRN. In some patients, they found that GCase was actually present and functional (which contradicted the traditional hallmark for Gaucher’s), but PGRN was not. Upon further research, they indicated that PGRN was the factor responsible for localizing GCase to lysosomes (where it does its job). Therefore, it turns out that patients could indeed have a normal GCase, but it does not end up where it is functional, which also leads to Gaucher’s. Aside from this, PGRN has another important function that links it to Gaucher’s. It is shown to recruit a repairer (chaperone) of GCase if it does not function properly over time. This provides another role for PGRN in preventing from Gaucher’s and insuring proper GCase activity.

When talking about Gaucher’s Type 1, its symptoms are traditionally associated with enlargement of the liver and spleen. Recently however, Gaucher’s has been also associated with inflammation (swelling, redness) – though the mechanism for this had not been understood. In 2015, a study illustrated that one of the two products (ceramide) of the breakdown of glucosylceramide by GCase suppresses a factor that induces inflammation. Therefore, when GCase is non-functional in Gaucher’s Disease, not only is there excess glucosylceramide, but also a deficiency in the products of glucosylceramide breakdown. This in turn promotes inflammation, and supports the characterization of Gaucher’s as an inflammatory disease. 

Recent studies have also increasingly linked Gaucher’s Disease to other famous diseases such as Parkinson’s Disease. This disease is characterized by stiffness and slowing of movement, typically more prevalent with age. In 2016, a study proposed a mechanism in which non-functional GCase is directly linked to symptoms of Parkinson’s disease. Conversely, when GCase is restored, these symptoms are relieved. Ultimately, it was found that GCase processes a main factor that causes Parkinson’s and prohibits it from taking place, therefore preventing individuals from the disease.

Fortunately, there has been a couple ways to treat Gaucher’s. The first treatment (called Substrate Reduction Therapy) is to prevent glucosylceramide from accumulating by targeting its production. The second is called Enzyme Repacement Therapy, which is accomplished by taking doses of functional GCase. Though, these both have many side effects and are not effective against the associated diseases discussed. Thus, the field is currently focusing on newer therapies that introduce repairers (chaperones) of both existing GCase and factors not only linked to Gaucher’s, but other diseases like Parkinson’s as well.

For further information, please visit my Theme Pages and access the PDF version of the infographic above Gaucher’s Disease Infographic.

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