Neurodegenerative disorders: Hunting glycoproteins
The complete set of the main brain glycoproteins has just been characterized in an attempt to uncover any defects in the glycosylation process that lead to neurodegenerative disorders.
Glycosylation is a feature of several of the proteins that are involved in the pathogenesis of Alzheimer's disease (AD), and aberrant glycosylation probably contributes to the generation of amyloid plaques and neurofibrillary tangles in the brain. To investigate this phenomenon, Huang and colleagues have set out to characterize all of the main brain glycoproteins, and their initial findings were recently reported in the European Journal of Neuroscience. Although this study has not yet uncovered any defects in the glycosylation process itself, the researchers did identify one important glycoprotein that was upregulated in AD.
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Huang et al. used affinity chromatography to isolate glycoproteins from post-mortem cerebral cortical tissue. The glycoproteins were separated using SDS-polyacrylamide gel electrophoresis and analysed by mass spectrometry. Eleven glycoproteins were isolated, one of which — the  -subunit of the lysosomal enzyme acid ceramidase — showed increased expression levels and activity in the brains of individuals with AD.
The authors next compared the distribution of acid ceramidase in brain tissue from control individuals and patients with AD. In both cases, the enzyme was expressed in most neurons and some astrocytes, and in the tissue from individuals with AD it showed marked co-localization with the intracellular neurofibrillary tangles. This might imply that acid ceramidase is somehow involved in neurofibrillary degeneration. However, its increased expression and activity could also be a protective response to AD-associated ceramide accumulation in the brain. Ceramide induces neuronal apoptosis, but acid ceramidase catalyses its conversion to sphingosine-1-phosphate — an anti-apoptotic agent.
Further studies will be required to determine the true significance of the elevated acid ceramidase levels. It will also be interesting to analyse the other glycoproteins that were isolated in this screen to find out whether any of them show defects in glycosylation in the brains of individuals with AD.
Heather Wood
References
- Huang, Y. et al. Elevation in the level and activity of acid ceramidase in Alzheimer's disease brain. Eur. J. Neurosci. 20, 3489–3497 (2004) | Article | PubMed |
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