Abstract
Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.
Highlights
Gaucher disease (GD), the most common lysosomal storage disease (LSD), is caused by mutations in the GBA1 gene, which encodes for glucosylceramidase (GlcCerase), the lysosomal hydrolase responsible for glucosylceramide (GlcCer) degradation [1]
The samples were collected under a study that was overseen by the Institutional Review Board (IRB) of the National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Health (NIH)
Quantitative global proteomic analysis of cerebrospinal fluid (CSF) samples from four type 3 GD patients and 5 agematched controls was performed. 489 proteins were identified in CSF but only 7 proteins were elevated more than 2-fold (Table 1), and levels of 10 proteins were reduced
Summary
Gaucher disease (GD), the most common lysosomal storage disease (LSD), is caused by mutations in the GBA1 gene, which encodes for glucosylceramidase (GlcCerase), the lysosomal hydrolase responsible for glucosylceramide (GlcCer) degradation [1]. GD is classically divided into three clinical sub-types based on age of onset and on signs of nervous system involvement [2]. Type 1 is the chronic, non-neuronopathic form and types 2 and 3 are the acute and chronic neuronopathic forms, respectively, which display central nervous system (CNS) involvement in addition to systemic disease [3], and are collectively known as neuronopathic GD (nGD). The disease encompasses a wide spectrum of phenotypes and a great diversity in severity and symptoms is observed in patients classified as the same sub-type. The PLOS ONE | DOI:10.1371/journal.pone.0120194 March 16, 2015
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