Disrupted Glycosylation of Lipids and Proteins Is a Cause of Neurodegeneration

Tobias Moll; Pamela J. Shaw; Johnathan Cooper-Knock

Disclosures

Brain. 2020;143(5):1332-1340. 

In This Article

Conclusions

Overall there is substantial evidence for dysfunction of glycosyltransferases in neurodegenerative diseases including ALS, Alzheimer's disease, Huntington's disease and Parkinson's disease. There are diverse functions associated with glycosyltransferase activity and for many of the enzymes the biological pathway associated with their activity is not yet clear. However, in our analysis, dysfunction associated with neurodegenerative disease can be seen to converge on the ganglioside synthesis pathway and altered O-GlcNAcylation. The exact nature of the defect appears to be variable in different diseases; for example ganglioside concentrations are reduced in Parkinson's disease and Huntington's disease, increased in Alzheimer's disease and there is evidence for change in both directions in ALS. Similarly, increased O-GlcNAcylation is associated with the development of Parkinson's disease pathology but reduced O-GlcNAcylation is associated with the development of tau pathology. We suggest that consensus will arise via efforts to position glycosyltransferase dysfunction within the cascade of pathogenesis leading to neuronal death—it is not glycosyltransferase dysfunction per se that is interesting, but rather upstream changes in glycosyltransferase function that initiate toxicity. With this in mind we have highlighted genetic associations between mutations in glycosyltransferases and neurodegenerative disease. Most prominently we have recently discovered autosomal dominant mutations in GLT8D1 to be a monogenic cause of ALS. Disease-associated mutations have also been discovered in UGT8 and ST6GAL1; and we have revealed a new association between ALS and mutations in EOGT. Glycosyltransferases are likely to be an important therapeutic target in the effort of develop disease-modifying therapies for neurodegenerative disease.

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