Disrupted Glycosylation of Lipids and Proteins Is a Cause of Neurodegeneration

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


Brain. 2020;143(5):1332-1340. 

In This Article

Glycosyltransferase O-GlcNAcylation: A Key Regulator of Neurodegeneration?

Protein glycosylation and more specifically the addition of O-GlcNAc groups to CNS proteins important for axonal and synaptic function, is significantly reduced in animal models of neurodegenerative diseases and in patient tissue from diseases including Huntington's disease, Alzheimer's disease and ALS (Liu et al., 2004; Ludemann et al., 2005; Kumar et al., 2014; Frenkel-Pinter et al., 2017) (Table 1). O-GlcNAcylation is reported to negatively regulate tau phosphorylation (Liu et al., 2004), which is key in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer's disease. In contrast, an increase in O-GlcNAcylation is observed in the post-mortem temporal cortex of patients with Parkinson's disease and is postulated to contribute to neurodegeneration through the inhibition of autophagy leading to an increase in α-synuclein accumulation (Wani et al., 2017). Neurofilaments are critical components of the neuronal cytoskeleton that can undergo O-GlcNAcylation (Yuan et al., 2012). Neurofilament levels are significantly higher in the serum and CSF of ALS patients compared to control subjects (Benatar et al., 2018). This increase is thought to be a consequence of axonal damage. However, there is evidence that neurofilament damage may be upstream in the pathogenesis of ALS including the observation that increased phosphorylation of neurofilaments is associated with neurotoxicity (Julien, 1997). It is thought that phosphorylation and O-GlcNAcylation are reciprocal, meaning that reduced O-GlcNAcylation could precipitate harmful phosphorylation; indeed this has been observed in a transgenic rat model of SOD1-ALS (Ludemann et al., 2005).

O-GlcNAcylation occurs predominantly in the brain and is regulated by the glycosyltransferases OGT and EOGT; the reverse reaction is catalysed by O-GlcNAcase (OGA). Together these reactions constitute a dynamic and reversible process (Figure 2). OGT is an inverting enzyme and a member of glycosyltransferase family 41; OGT is highly enriched in the brain, where it is 10 times more active than in peripheral tissue (Okuyama and Marshall, 2003). OGT is localized to the nucleus, soma, dendrites and presynaptic terminals of neurons (Akimoto et al., 2003). Removal of postsynaptic OGT from primary neurons inhibits both synapse formation and the development of dendritic spines (Lagerlof et al., 2017). This highlights the importance of OGT in maintaining synaptic stability, and notably loss of synaptic stability is a unifying feature of neurodegenerative disease. EOGT is an inverting enzyme and a member of glycosyltransferase family 61. Despite distinct sites of action, OGT and EOGT are both regulated via the hexosamine biosynthetic pathway (Ogawa et al., 2015). EOGT activity is involved in Notch signalling, which is important for neurodevelopment. Indeed, homozygous loss-of-function mutations in EOGT produce Adams-Oliver syndrome, a congenital developmental disorder associated with actin cytoskeleton defects.

ALS-associated Genetic Variants Within O-GlcNAcylation Pathway Enzymes

While homozygous EOGT mutations affect neurodevelopment, we hypothesized that heterozygous mutations within EOGT might negatively impact on the maintenance of axon integrity and increase risk of developing ALS. To test this hypothesis we performed rare-variant burden testing (Cirulli et al., 2015) within EOGT to check for a genetic association with ALS. We used whole genome sequencing data from 4493 sporadic ALS patients and 1924 control subjects (van der Spek et al., 2019); we identified 32 missense rare (MAF < 1%) variants within EOGT that were exclusively or predominantly found in ALS cases (Table 2). When considering all rare missense variants found in cases and controls across all exons of EOGT, there was a significant enrichment of such mutations in ALS patients (Firth logistic regression, P = 0.007). Similar testing did not identify an enrichment of ALS-associated mutations within OGT, indeed we only identified two rare missense mutations within OGT in 4493 sporadic ALS patients. It should be noted that OGT is encoded on the X chromosome and therefore males are necessarily hemizygous, which may predispose to a neurodevelopmental phenotype rather than a late age-of-onset disease: for example mutations within N-terminal tetratricopeptide repeats of OGT are associated with X-linked intellectual disability (Gundogdu et al., 2018). There was no significant burden of ALS-associated mutations within OGA (P = 0.91).