Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease
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LEADING ARTICLE
Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease Elisa Menozzi1 · Anthony H. V. Schapira1
© Springer Nature Switzerland AG 2020
Abstract Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD), characterized by deficient activity of the glucocerebrosidase enzyme (GCase). Both individuals with GD type I and heterozygous carriers of pathogenic variants of GBA1 have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients without GBA1 mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect α-synuclein pathology in different ways. Misfolded GCase proteins are retained in the endoplasmic reticulum, altering the lysosomal trafficking of the enzyme and disrupting protein trafficking. Also, deficient GCase leads to accumulation of substrates that in turn may bind α-synuclein and promote pathological formation of aggregates. Furthermore, α-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and α-synuclein. Targeted therapies aimed at enhancing GCase activity, augmenting the trafficking of misfolded GCase proteins by small molecule chaperones, or reducing substrate accumulation, have been tested in preclinical and clinical trials. This article reviews the molecular mechanisms linking GCase to α-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.
Key Points
1 Introduction
Mutations in the GBA1 gene, encoding for the lysosomal enzyme glucocerebrosidase, are the most common genetic risk factor for Parkinson disease.
“There appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least, the progress of the disease may be stopped”. After more than 200 years since James Parkinson wrote this prediction, we are now living in a time when the chance to slow the progression of Parkinson disease (PD) is probably more than just a hope. Novel treatments manipulating the pathway involving Glucocerebrosidase enzyme (GCase), encoded by the glucocerebrosidase (GBA1) gene, offer potential to slow or even prevent PD in both individuals with and without GBA1 mutations. In this article, we provide an overview of the epidemiological burden of GBA1 mutations in the PD population, review the mechanisms by which GCase dysfunction is thought to impact PD onset and progression, and conclude by examining the available treatments for PD that target the GCase pathway.
A complex interaction exists between glucocerebrosidase and α-synuclein. Gene therapy, small molecule chaperones and modulators targeting the glucocerebrosidase pathway, are promising therapies for Parkinson disease
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