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Gaucher and Parkinson's disease

The link between the GBA (glucocerebrosidase) gene and parkinsonism

Dr Ellen Sidransky MD and Grisel Lopez MD

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.

The following are published articles on studies reporting the association between Gaucher disease and the development of Parkinson's disease.

The Genetics of Parkinson's Disease - Dr. Ellen Sidransky

Acid β-glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α-synuclein processing

Occurrence of Parkinson's syndrome in type 1 Gaucher disease

Parkinsonism among Gaucher disease carriers

Mutations for Gaucher Disease Confer High Susceptibility to Parkinson Disease

Increased incidence of Parkinson disease among relatives of patients with Gaucher disease

Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism

Parkinsonism among Gaucher disease carriers

Overworked Cellular Machines May Explain Gaucher Disease Link to Parkinson's Disease