Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

Abstract

Gaucher disease (GD) is an inherited disorder caused by recessive mutations in the GBA1 gene that encodes the lysosomal enzyme β-glucocerebrosidase (β-GC). β-GC hydrolyzes glucosylceramide (GluCer) into glucose and ceramide in the lysosome, and the loss of its activity leads to GluCer accumulation in different tissues. In severe cases, enzymatic deficiency triggers inflammation, organomegaly, bone disease, and neurodegeneration. Neuronopathic Gaucher disease (nGD) encompasses two different forms of the disease, characterized by chronic or acute damage to the central nervous system (CNS). The cellular and molecular studies that uncover the pathological mechanisms of nGD mainly focus on lysosomal dysfunction since the lysosome is the key organelle affected in GD. However, new studies show alterations in other organelles that contribute to nGD pathology. For instance, abnormal accumulation of GluCer in lysosomes due to the loss of β-GC activity leads to excessive calcium release from the endoplasmic reticulum (ER), activating the ER-associated degradation pathway and the unfolded protein response. Recent evidence indicates mitophagy is altered in nGD, resulting in the accumulation of dysfunctional mitochondria, a critical factor in disease progression. Additionally, nGD patients present alterations in mitochondrial morphology, membrane potential, ATP production, and increased reactive oxygen species (ROS) levels. Little is known about potential dysfunction in other organelles of the secretory pathway, such as the Golgi apparatus and exosomes. This review focuses on collecting evidence regarding organelle dysfunction beyond lysosomes in nGD. We briefly describe cellular and animal models and signaling pathways relevant to uncovering the pathological mechanisms and new therapeutic targets in GD.

A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach

“…Farfel-Becker et al used a mouse model of GD2 and observed that when the continuous neuronal accumulation of GlcCer reaches a certain level, a rapid cascade of neuroinflammation and neurodegeneration is induced in particular regions of the brain and may lead to neuronal cell death 78 , 79 . The symptoms of GD2 include progressive cognitive decline, muscle stiffness, loss of motor skills, difficulty in coordination, respiratory difficulties, and swallowing disorders along with the systemic manifestation of GD 80 , 81 . There are several phenotypes associated with GD2: hydrops fetalis- a condition when an excessive buildup of fluid in various parts of the body occurs; hepatosplenomegaly; skin abnormalities including congenital ichthyosis and abnormal, cellophane-like skin; dysmorphology of face features 82 ; neurological involvements such as joint contractures, decreased body movements, etc.…”

The molecular mechanism of Gaucher disease caused by compound heterozygous mutations in GBA1 gene

“…However, its frequency is as high as 1:800 in Ashkenazi Jews ( 1 ). GD is caused by mutations in GBA1 (OMIM #606463), which encodes the lysosomal enzyme glucocerebrosidase (GCase) ( 2 ). To date, more than 500 mutations have been described in the GBA1 gene, including single base changes, splicing alterations, partial and total deletions, insertions, and rearrangements ( 3 , 4 ).…”

Multiplex Quantification of Plasma Biomarkers for Patients with Gaucher Disease Type 1

“…GD is characterized by marked phenotypic and genotypic variability (D'Amore et al., 2021; Grabowski et al., 2021; Özdemir, 2022). Over 300 different mutations have been described for the GBA gene (D'Amore et al., 2021) and result in phenotypes ranging from asymptomatic to in‐utero death (Arévalo et al., 2022; Weinreb et al., 2021. Although GD phenotypes span a wide continuum, three types can be distinguished (Schiffmann et al., 2020; Silva García et al., 2021).…”

“…GD is characterized by marked phenotypic and genotypic variability (D'Amore et al, 2021;Grabowski et al, 2021;Özdemir, 2022). Over 300 different mutations have been described for the GBA gene (D'Amore et al, 2021) and result in phenotypes ranging from asymptomatic to in-utero death (Arévalo et al, 2022;Weinreb et al, 2021. Although GD phenotypes span a wide continuum, three types can be distinguished (Schiffmann et al, 2020;Silva García et al, 2021). Type 1 GD (OMIM 230800) accounts for approximately 90% to 95% of all GD cases, with an estimated disease prevalence of 1 in 52,000 individuals in the general population (Biegstraaten et al, 2018;Chis, Chis, and Dumitrascu, 2021;Giraldo, 2021).…”