GBA1 Gene Mutations in α-Synucleinopathies-Molecular Mechanisms Underlying Pathology and Their Clinical Significance

Abstract

α-Synucleinopathies comprise a group of neurodegenerative diseases characterized by altered accumulation of a protein called α-synuclein inside neurons and glial cells. This aggregation leads to the formation of intraneuronal inclusions, Lewy bodies, that constitute the hallmark of α-synuclein pathology. The most prevalent α-synucleinopathies are Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). To date, only symptomatic treatment is available for these disorders, hence new approaches to their therapy are needed. It has been observed that GBA1 mutations are one of the most impactful risk factors for developing α-synucleinopathies such as PD and DLB. Mutations in the GBA1 gene, which encodes a lysosomal hydrolase β-glucocerebrosidase (GCase), cause a reduction in GCase activity and impaired α-synuclein metabolism. The most abundant GBA1 gene mutations are N370S or N409S, L444P/L483P and E326K/E365K. The mechanisms by which GCase impacts α-synuclein aggregation are poorly understood and need to be further investigated. Here, we discuss some of the potential interactions between α-synuclein and GCase and show how GBA1 mutations may impact the course of the most prevalent α-synucleinopathies.

Keywords: GBA1 mutations; Gaucher’s disease; Parkinson’s disease; dementia with Lewy bodies; glucocerebrosidase; glycosylceramidase; multiple system atrophy; α-Synuclein; α-synucleinopathies.

Figure 1

The structure of the GBA1 gene and the encoded GBA1 protein (β-glucocerebrosidase/GCase). GBA1 gene, located at q21 region of chromosome 1, comprises 13 exons and 2 promoters (P1 and P2), and is characterized by multiple splicing variants and transcription start sites. GBA1 protein is composed of three main regions: 39-residue signal peptide, the conserved catalytic domain Glyco_hydro_30 (329 aa) and Glyco_hydro_30C domain (30C in the picture; 62 aa). The mature GBA1 protein—GCase—is composed of 497 amino acids (residues 40–536) and it includes Glyco_hydro_30 and 30C regions.

Figure 2

The schematic representation of major molecular consequences induced by GBA1 mutations. The structure of the GBA1 protein is presented in the middle (PDB ID: 1OGS). Mutations in GCase usually result in significant decrease in enzyme activity, that in turn greatly impacts the functionality of autophagy–lysosomal system (ALS); this affects lipid homeostasis due to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) as well as facilitates aggregation of α-synuclein (α-syn). Excessive accumulation of lipids and abnormal proteins within the cell induces endoplasmic reticulum (ER) stress conditions and cause damage to the mitochondria. All mentioned events lead to induction of neuroinflammatory response with subsequent activation of NLRP3 inflammasome.

Figure 3

Molecular mechanisms underlying GCase mutations and the associated cellular events. Under normal conditions, the functional GCase is synthesized in the ER, bound to lysosomal integral membrane protein type-2 (LIMP-2) and transferred to the Golgi apparatus for glycosylation. Then, it is targeted to the lysosomes, where it catalyzes degradation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) to glucose and ceramide or glucose and sphingosine, respectively; Saposin C (SapC) acts as a cofactor in this process. However, in the case of mutant GCase, the activity of enzyme is markedly decreased, which leads to accumulation of GlcCer and GlcSph, and in consequence—lipid imbalance. Impaired function of GCase also affects the degradation of other lysosomal substrates, such as α-synuclein oligomers. Accumulation of mutant GCase and α-synuclein within the cell contribute to endoplasmic reticulum (ER) stress, as well as mitochondria swelling and dysfunction. Moreover, α-synuclein aggregates inhibit the GCase transport from ER to Golgi, which further decreases GCase activity and generates a bi-directional positive feedback loop.