Altered protein glycosylation predicts Alzheimer's disease and modulates its pathology in disease model Drosophila

Moran Frenkel-Pinter, Shiri Stempler, Sharon Tal-Mazaki, Yelena Losev, Avnika Singh-Anand, Daniela Escobar-Álvarez, Jonathan Lezmy, Ehud Gazit, Eytan Ruppin, Daniel Segal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The pathological hallmarks of Alzheimer's disease (AD) are pathogenic oligomers and fibrils of misfolded amyloidogenic proteins (e.g., β-amyloid and hyper-phosphorylated tau in AD), which cause progressive loss of neurons in the brain and nervous system. Although deviations from normal protein glycosylation have been documented in AD, their role in disease pathology has been barely explored. Here our analysis of available expression data sets indicates that many glycosylation-related genes are differentially expressed in brains of AD patients compared with healthy controls. The robust differences found enabled us to predict the occurrence of AD with remarkable accuracy in a test cohort and identify a set of key genes whose expression determines this classification. We then studied in vivo the effect of reducing expression of homologs of 6 of these genes in transgenic Drosophila overexpressing human tau, a well-established invertebrate AD model. These experiments have led to the identification of glycosylation genes that may augment or ameliorate tauopathy phenotypes. Our results indicate that OstDelta, l(2)not and beta4GalT7 are tauopathy suppressors, whereas pgnat5 and CG33303 are enhancers, of tauopathy. These results suggest that specific alterations in protein glycosylation may play a causal role in AD etiology.

Original languageAmerican English
Pages (from-to)159-171
Number of pages13
JournalNeurobiology of Aging
Volume56
DOIs
StatePublished - Aug 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • Alzheimer's disease
  • Drosophila
  • Glycosylation
  • Tau
  • Tauopathy

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