Editors' ChoiceGaucher's and Parkinson's Disease

Gaucher's and Parkinson's Disease: Together at Last

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Science Translational Medicine  04 Nov 2009:
Vol. 1, Issue 5, pp. 5ec17
DOI: 10.1126/scitranslmed.3000546

Bench-to-bedside is a phrase currently in vogue when we talk about translation. But sometimes research begins in the clinic and heads the other way. In this week's issue of the New England Journal of Medicine, Sidransky et al. tell the latest multicultural installment of a story that started with a handful of case studies chronicling Parkinsonism in patients with Gaucher's disease.

Gaucher's is an autosomal recessive lysosomal storage disorder that arises from mutations in the gene that encodes glucocerebrosidase (GBA), an enzyme that breaks down the glycolipid glucocerebroside into glucose and ceramide. When this enzyme is defective, glucocerebroside accumulates in several organs, disrupting their function. Several lines of investigation have zeroed in on an association between Gaucher's and Parkinson's disease (PD). First, PD symptoms were noted in a small number of patients with Gaucher's disease. Pedigree studies later revealed that relatives of Gaucher patients displayed inflated incidences of PD. Then, investigations of individual cohorts of PD patients suggested an enhanced frequency of GBA mutations. But genome-wide association studies have failed to link mutated GBA alleles with PD. Sixteen centers from around the world joined forces in the current study of 5,691 PD patients and 4,898 control individuals. Their analyses unearthed two GBA point mutations in ethnically diverse populations that were strongly associated with PD, yielding an odds ratio of 5.43 for GBA mutations in patients versus controls. PD patients with GBA mutations displayed a significantly earlier age at disease onset. And among patients with detailed family histories (4,401), 24 and 18 percent of patients with or without GBA mutations, respectively, declared that they had a first- or second-degree relative with PD, a significant difference. It remains unclear how this association is manifest in PD patients. But two provocative hypotheses are that GBA mutations give rise to increased protein aggregation or changes in amounts of ceramide, an important player in several signal transduction pathways.

E. Sidransky et al., Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361, 1651–1661 (2009). [Abstract]

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