The link between the GBA gene and parkinsonism

Abstract

Mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is deficient in Gaucher's disease, are important and common risk factors for Parkinson's disease and related disorders. This association was first recognised in the clinic, where parkinsonism was noted, albeit rarely, in patients with Gaucher's disease and more frequently in relatives who were obligate carriers. Subsequently, findings from large studies showed that patients with Parkinson's disease and associated Lewy body disorders had an increased frequency of GBA mutations when compared with control individuals. Patients with GBA-associated parkinsonism exhibit varying parkinsonian phenotypes but tend to have an earlier age of onset and more associated cognitive changes than patients with parkinsonism without GBA mutations. Hypotheses proposed to explain this association include a gain-of-function due to mutations in glucocerebrosidase that promotes α-synuclein aggregation; substrate accumulation due to enzymatic loss-of-function, which affects α-synuclein processing and clearance; and a bidirectional feedback loop. Identification of the pathological mechanisms underlying GBA-associated parkinsonism will improve our understanding of the genetics, pathophysiology, and treatment for both rare and common neurological diseases.

Figure 1. The 16 centres that participated in the international collaborative study on the frequency of GBA mutations in Parkinson’s disease

The numbers shown are the number of patients from each centre. Numbers in parentheses are the number of GBA mutation carriers identified at each site. Numbers in red show centres that sequenced the GBA gene for genotyping.

Figure 2. Immunofluorescence assessment of glucocerebrosidase in Lewy bodies in patients with parkinsonism without and with GBA mutations

(A, B, and C) The substantia nigra area from a patient without GBA mutations stained for glucocerebrosidase (A, red) and α-synuclein (B, green). The merged image with the nuclear stain (blue) shows a paucity of glucocerebrosidase staining in the Lewy body structure (C). (D, E, and F) The substantia nigra area from a GBA mutation carrier stained for glucocerebrosidase (D, red) and α-synuclein (E, green) showing colocalisation and accumulation in the Lewy body structure (F).

Figure 3. The bidirectional loop theory

Decreased glucocerebrosidase increases the lysosomal concentrations of glucosylceramide, which increases the formation of soluble α-synuclein oligomers. These oligomers also disrupt transport of newly synthesised glucocerebrosidase between the endoplasmic reticulum and Golgi apparatus, further compounding the problem.

Figure 4. How mutant glucocerebrosidase might result in enhanced α-synuclein aggregation

(A) In the normally functioning lysosome, wild-type glucocerebrosidase might interact with α-synuclein, facilitating the lysosomal component of α-synuclein degradation. (B) In most cases, when glucocerebrosidase is mutated, α-synuclein remains in the monomeric form and other processes are active in its degradation. (C) In some patients, glucocerebrosidase is mutated and the cell is unable to degrade α-synuclein. Lysosomal function is compromised and increased oligomeric forms of α-synuclein lead to neuronal cell death and the development of parkinsonism. This situation might enhanced by ageing, when the number of lysosomes and lysosome function decrease and cellular α-synuclein concentrations increase.