2. Gaucher’s Disease (Type 1): Mechanism and Pathophysiology

As mentioned in Overview/Structural Biology, when an excess of unhydrolyzed glucosylceramide (glucocerebroside) lipids is found in macrophages, the cells transform into Gaucher cells. The accumulation of these lipids because of GCase impairment is believed to be the hallmark of Gaucher’s disease, and the traditional understanding and explanation for its manifestation (Figure 1). Recently though, Gaucher’s disease has been characterized as an inflammatory disease, but with no underlying mechanism to explain this. In 2015, Kitatani et al. actually resolved this issue and presented significant evidence to support the emergence of Gaucher’s as an inflammatory disease. Particularly, they found that p38 pro-inflammatory kinase levels were increased in liver and lung tissues in mice with Gaucher’s Disease Type 1, but not in the brain (which was the case for Types 2 and 3 only) (Kitatani et al. 2015). Considering that p38 is believed to serve as a key kinase that promotes the formation of Interleukin 6 (IL-6) (which acts itself as a pro-inflammatory cytokine), this explained why patients with Gaucher’s disease also had high levels of IL-6 (Kitatani et al. 2015). Using these two pieces of information together, along with the fact that ceramide has been proposed to suppress p38 activation, the authors propose a model for inflammation in Gaucher’s disease. Since hydrolysis of glucosylceramide is hindered in Gaucher’s disease, there is a deficiency in ceramide product that suppresses p38. This in turn leads to enhanced activation of p38 kinase, which leads to the formation of excess IL-6 and thus pro-inflammatory symptoms (Kitatani et al. 2015).

Figure 1. Traditional view of Gaucher’s: (A) Deficiency of GCase leads to accumulation of glucosylceramide (glucocerebroside), which causes enlargement of macrophages and formation of Gaucher cells in spleen and liver tissues (B) (Stirnemann et al., 2017). 

In continuing the quest to go beyond the traditional explanation for Gaucher’s and to discover the unknown mechanisms of the disease, Jian et al. attempted to study a previously unrecognized factor that was thought to associate with Gaucher’s disease (progranulin, PGRN) and characterize its function. PGRN is known to be widely expressed in epithelial cells, chondrocytes and in cells of the immune system, and is shown to be critical in early embryogenesis, wound healing and host defense (Jian et al. 2016). Further, previous studies have demonstrated an association between PGRN insufficiency and GD; however, the mechanism underlying this association remained unclear (Jian et al. 2016). Therefore, the study by Jian et al. was very significant for many reasons. First, it illustrates that PGRN promotes lysosomal localization of GCase through directly interacting with the enzyme (Figure 2). This meant that GCase is not necessarily deficient in Gaucher’s patients, but rather is not being directed properly to its target due to deficiency in PGRN (Jian et al. 2016). Second, the study found that heat shock protein 70 (HSP70), a highly conserved molecular chaperone that mediates folding and unlocks disaggregation of numerous proteins, associates with the complex of GCase and its receptor LIMP2 depending on the presence of PGRN (Jian et al. 2016). Under stressed conditions in normal cells, the GCase/LIMP2 complex aggregates in the cytoplasm, and HSP70 is recruited to the GCase/LIMP2 complex through PGRN, acting as an indispensable co-chaperone to dismantle the aggregated complex (Jian et al. 2016). However, as previously mentioned, PGRN is deficient in Gaucher’s patients. Therefore, HSP70 does not get recruited to remove GCase/LIMP2 cytoplasmic aggregates, which in turn induces Gaucher’s disease phenotypes (Jian et al., 2016). Altogether, the study provides a new mechanistic understanding for Gaucher’s, as PGRN both recruits GCase to the lysosome and indirectly removes GCase/LIMP2 complex aggregates in the cytoplasm. It also provides the potential for treatment against Gaucher’s, as chaperones can be used to rescue protein aggregation associated with this disease (more in Current/Future Treatments).

Figure 2. PGRN co-localizes with GCase in lysosome and ER of macrophage in WT mice lung tissue. PGRN is the 18 nm particle (large) and GCase is the 5 nm particle (small), co-localizations are indicated by arrows (Jian et al. 2016).

With more progress being made in discovering the different factors that lead to Gaucher’s, scientists sought to contribute to new knowledge by explaining the missing link between Gaucher’s and Parkinson’s disease. Historically, Gaucher’s disease and mutations in the GBA1 gene have been directly linked to Parkinson’s disease; however, the role of these GBA1 mutations in the pathogenesis of Parkinson’s has not been fully understood (Rockenstein et al. 2016). In 2016, Rockenstein et al. examine the hypothesis that suggests that a decrease in glucocerebrosidase activity (which is the case in Gaucher’s disease) induces an increase in α-synuclein aggregates, the pathological hallmark of Parkinson’s disease. The authors modulated disease progression in two mouse models with α-synuclein aggregates that harbored wild-type Gba1 alleles (do not have Gaucher’s disease). Consequently, they found that reduction of GCase activity actually led to the development of motor morbidities associated with Parkinson’s disease (Rockenstein et al. 2016). Further, increasing the enzymatic activity of GCase delayed the progression of Parkinson’s disease. Therefore, this study supports a role for glucocerebrosidase activity in α-synuclein processing and prevention from aggregation, independent of mutations in GBA1 (Rockenstein et al. 2016). In addition, it explains the link between Gaucher’s disease and Parkinson’s disease, as GCase deficiency in the former leads to aggregation of α-synuclein and thus early onset of Parkinson’s.

In addition to Parkinson’s, Gaucher’s disease has also been shown to induce some metabolic abnormalities. Specifically, increased serum ferritin (which is an iron-binding protein that stores iron in a biologically available form to avoid toxicity) is frequent in Gaucher’s disease Type 1 (Medrano-Engay et al. 2014). In understanding this, Medrano-Engay et al. observed that some Gaucher cells have increased synthesis of hepcidin, an inhibitor of intestinal absorption of iron. As discussed earlier, cytokine production is upregulated in Gaucher’s disease. These cytokines in turn increase the transcription of the hepcidin gene in patients with this disease (Medrano-Engay et al. 2014). As a result, iron retention is increased, which leads to high levels of serum and liver ferritin (a condition called hyperferritinemia) (Medrano-Engay et al. 2014). This is important considering that iron overload damages cells by catalyzing reactive oxygen species, which are linked to mitochondrial and nuclear DNA damage and aging.

Moreover, various studies also point to other metabolic syndromes in Type 1 Gaucher’s. These syndromes include propensity to cholesterol GS, low high-density lipoprotein (HDL) cholesterol, LDL cholesterol, and body mass index (BMI) associated with abnormal biliary lipid secretion (Taddei et al., 2010). Accumulation of the precursor glucocerebroside has been linked to accumulation of its metabolite (ganglioside, GM3) in the lipid rafts surrounding insulin receptors, which leads to insulin resistance and therefore these syndromes (Taddei et al., 2010). Altogether, these mechanistic understandings provide a more in-depth explanation for Gaucher’s, which can help in developing different therapies and methods to combat this pathology, as will be discussed more in Current and Future Treatments.

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3 Responses to 2. Gaucher’s Disease (Type 1): Mechanism and Pathophysiology

  1. Elijah Sommer says:

    Hi John! The pathophysiology of Gaucher’s really is fascinating; this is great work! I’m interested to know more about the mechanism by which the enzyme GCase interacts with and affects α-synuclein processing. Thanks!
    -Eli Sommer

  2. Gianna Barres says:

    Hi John!

    This is great! I am wondering how the GCase enzyme decreases the levels of alpha-synuclein that are associated with Parkinson’s disease?

    All the best,
    Gianna

    • admin says:

      Hi Gianna!

      Thank you for your comment! To answer your question, I found a recently published paper that might help in clarifying the connection between GCase and alpha-synuclein (see link below). In Gaucher’s, the substrate glucosylceramide accumulates due to the decreased functioning of GCase. This accumulation is thought to stabilize the toxic oligomeric forms of alpha-synuclein, which in turn negatively influence the activity of GCase even further and block the export of the newly synthesized enzyme from the endoplasmic reticulum to late endocytic compartments. This amplifies the pathological effects of alpha-synuclein, which results in neuronal cell death. Altogether, this pathogenic molecular feedback loop shifts the cellular homeostasis from monomeric alpha-synuclein towards oligomeric (neurotoxic) and aggregated forms, which contribute to Parkinson’s disease progression. Hope this helps!
      https://www.ncbi.nlm.nih.gov/pubmed/26860955

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