Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase are important risk factors for the development of Parkinson disease (PD) and related disorders. This association is based upon the concurrence of parkinsonism and Gaucher disease (GD), an increased incidence of PD in Gaucher carriers, and neuropathological findings [1
]. Furthermore, multiple independent studies indicate that patients with PD and related synucleinopathies have an increased frequency of GBA1
]. A recent multicenter collaborative study indicated that in PD, the odds ratio for carrying a GBA1
mutation is greater than 5, rendering mutations in this gene the most common genetic risk factors for parkinsonism identified to date [11
]. However, since the vast majority of patients with GD and GBA1
mutation carriers never develop parkinsonism, mutations in this gene are clearly a risk factor for PD, rather than a causative gene.
Gaucher disease, resulting from the inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCase), is a panethnic disorder with a broad spectrum of associated clinical presentations. Classically the disorder is divided into type 1 (non-neuronopathic), type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) forms. It is primarily a disorder of the reticuloendothelial system, and unlike other lysosomal storage disorders, lacks abundant storage of lipid in the brain. The neuropathology of neuronopathic GD disease includes periadventitial accumulation of lipid-laden macrophages (Gaucher cells), occasionally coupled with neuronal loss with crumpled, shrunken-atrophic neurons [3
]. Moreover, gliosis and neuronal loss are described in the hippocampal regions CA2-4 and calcarine layer 4. Several autopsy studies of patients with GBA1-
associated synucleinopathies indicate that there is a spectrum of associated neuropathologic findings. Most patients have Lewy bodies and Lewy neurites. In subjects with GD and parkinsonism, α-synuclein positive Lewy bodies are seen, as well as Lewy body-like synuclein inclusions in hippocampal pyramidal cell neurons [2
]. A recent immunofluorscence study, conducted on nine patients harboring GBA1
mutations, demonstrated that glucocerebrosidase was present in between 50 and 90% of the Lewy bodies, compared to less than 10% in subjects without mutations [12
One of the main features of α-synuclein is its tendency to aggregate into β-sheet-like oligomers. This procedure goes through several steps leading to the formation of the insoluble fibrils that form Lewy bodies. Aggregated α-synuclein is associated with cell death and neurodegeneration, and multiple systems and organelles can be affected by α-synuclein accumulation [13
]. The nature of the neurotoxicity associated with α-synuclein, mainly thought to be associated with the oligomeric forms, is a source of considerable debate [13
To probe whether similar biochemical changes characteristic of synucleinopathies were present in patients with GD, we evaluated levels of soluble and insoluble α-synuclein in brain samples from patients with GD with and without synucleinopathies.