Authors: Ozlem GokerAlpan Barbara K Stubblefield Benoit I Giasson Ellen Sidransky
Publish Date: 2010/09/14
Volume: 120, Issue: 5, Pages: 641-649
Abstract
Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase known to cause Gaucher disease GD are a risk factor for the development of Parkinson disease PD and related disorders This association is based on the concurrence of parkinsonism and GD the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world and neuropathologic findings The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia Three individuals had GD and four were heterozygous for glucocerebrosidase mutations All cases had no known family history of PD and the mean age of disease onset was 59 years range 42–77 Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32–90 of Lewy bodies mean 75 some ubiquitinated and others nonubiquitinated In samples from seven subjects without mutations 10 of Lewy bodies were glucocerebrosidase positive mean 4 This data demonstrates that glucocerebrosidase can be an important component of αsynucleinpositive pathological inclusions Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregatesWe thank Stephen Wincovitch for technical assistance with confocal microscopy and Julia Fekecs and Jae Choi for preparation of the figures This work was supported by the Intramural Research Program of the National Human Genome Research Institute and Udall Centre of Excellence in Parkinson’s Disease Research Grant NS053488
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