Glucocerebrosidase and its relevance to Parkinson disease

Abstract

Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson disease and related synucleinopathies. A great deal is known about GBA1, as mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease. Over the past decades, significant progress has been made in understanding the genetics and cell biology of glucocerebrosidase. A least 495 different mutations, found throughout the 11 exons of the gene are reported, including both common and rare variants. Mutations in GBA1 may lead to degradation of the protein, disruptions in lysosomal targeting and diminished performance of the enzyme in the lysosome.Gaucher disease is phenotypically diverse and has both neuronopathic and non-neuronopathic forms. Both patients with Gaucher disease and heterozygous carriers are at increased risk of developing Parkinson disease and Dementia with Lewy Bodies, although our understanding of the mechanism for this association remains incomplete. There appears to be an inverse relationship between glucocerebrosidase and α-synuclein levels, and even patients with sporadic Parkinson disease have decreased glucocerebrosidase. Glucocerebrosidase may interact with α-synuclein to maintain basic cellular functions, or impaired glucocerebrosidase could contribute to Parkinson pathogenesis by disrupting lysosomal homeostasis, enhancing endoplasmic reticulum stress or contributing to mitochondrial impairment. However, the majority of patients with GBA1 mutations never develop parkinsonism, so clearly other risk factors play a role. Treatments for Gaucher disease have been developed that increase visceral glucocerebrosidase levels and decrease lipid storage, although they have yet to properly address the neurological defects associated with impaired glucocerebrosidase. Mouse and induced pluripotent stem cell derived models have improved our understanding of glucocerebrosidase function and the consequences of its deficiency. These models have been used to test novel therapies including chaperone proteins, histone deacetylase inhibitors, and gene therapy approaches that enhance glucocerebrosidase levels and could prove efficacious in the treatment of forms of parkinsonism. Consequently, this rare monogenic disorder, Gaucher disease, provides unique insights directly applicable to our understanding and treatment of Parkinson disease, a common and complex neurodegenerative disorder.

Keywords: GBA1; Gaucher disease; Glucocerebrosidase; Lysosome; Parkinson disease; α-Synuclein.

Fig. 1

Simplified diagram of the synthesis and trafficking of GCase in a functional cell. 1) GBA1, the gene coding for GCase, is transcribed into mRNA that is then transported out of the nucleus to the ER. 2) GCase is synthesized in the ER, where it binds to the protein LIMP2 in the favorable neutral pH of the cytoplasm. 3) LIMP2 transfers GCase through the Golgi. 4) GCase is then transferred to a late endosome. 5) When the late endosome fuses with a lysosome to form an autolysosome, LIMP2 disengages from GCase due to the decrease in pH. In the lysosome, GCase is activated by SAPC. GCase actively hydrolyzes its substrates GlcCer and GlcSph in this compartment

Fig. 2

Reaction schema depicting the enzyme GCase hydrolyzing GlcCer and GlcSph. In the lysosome, GCase hydrolyzes substrates GlcCer (above) and GlcSph (below) by cleaving a glucose moiety off the molecule, creating the products glucose and ceramide, or glucose and sphingosine, respectively

Fig. 3

Scaled map of a 50 kb gene-rich region surrounding/antecedent to the GBA1 gene on chromosome 1q21. Genes represented above the line are transcribed right to left, while the genes below are transcribed left to right. Note the close proximity of GBA1 to its pseudogene with 98% homology, making it a common site for recombination events [9]

Fig. 4

Different hypothetical mechanisms by which GCase can be impaired, and various therapeutic approaches targeting these mechanisms. These include A) failure of the GCase protein to exit the ER, B) failure of GCase to link with its LIMP2 trafficking transporter, C) GCase is misfolded and unstable, so degraded through the unfolded protein response, D) failure of GCase to exit the Golgi, E) GCase is inactive due to mutations at the active site, and F) GCase activity is altered due to a Saposin C defect, and. The failure of GCase to reach the lysosome or be activated in the lysosome enables GlcCer and GlcSph to accumulate in the lysosome, creating the hallmark marker of Gaucher disease, Gaucher cells. Various therapies to address GCase impairment include: 1) Gene therapy: directly replacing mutant DNA with corrected DNA via adeno-associated or other viral infection. 2) Pharmacological chaperone therapy: introducing chaperone proteins to stabilize and refold misfolded proteins. 3) Histone deacetylase inhibitors: inhibiting unfolded protein response to allow more misfolded proteins to reach the lysosome. 4) Enzyme replacement therapy (ERT): replacing dysfunctional enzyme with recombinant enzyme targeted to the lysosome. 5) Substrate reduction therapy (SRT): reducing substrate accumulation regardless of GCase levels by inhibiting substrate synthesis. Currently, ERT and SRT are the only FDA-approved treatment options for patients with Gaucher disease