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

Genetic Mutations in Glycosyltransferases Cause Neurodegeneration

Genetic mutations in the development of an age-associated neurodegenerative disease are, by definition, upstream causes or risk factors rather than secondary to the disease process. Mutations discovered to date are included in Table 1 and described below.

GLT8D1

A recent study from our lab demonstrated that mutations within the glycosyltransferase domain of GLT8D1 are associated with familial ALS (Cooper-Knock et al., 2019). The function of GLT8D1 is unknown, but it is ubiquitously expressed and localized to the Golgi apparatus. Based on sequence homology, GLT8D1 is a member of glycosyltransferase family 8 and is expected to catalyse the transfer of a glycosyl group from a donor to an acceptor via a 'retaining' mechanism. Mutated GLT8D1 carrying ALS-associated amino acid changes is toxic to neuronal and non-neuronal cell lines, and induces motor deficits in zebrafish embryos; these observations are consistent with a role in motor neuron degeneration. Interestingly, relative toxicity of ALS-associated mutations in model systems mirrors the clinical severity. Glycosyltransferase enzyme activity is reduced in the mutated form of GLT8D1 commensurate with an increase in substrate affinity, which is predicted to impair cycling of substrate through the enzyme and thus reduce overall velocity (Cooper-Knock et al., 2019). Taken together, these data are consistent with loss-of-function toxicity. Our study is the first time inherited mutations that diminish glycosyltransferase enzyme activity have been associated with ALS. We have recently demonstrated by immunocytochemistry that ALS-associated mutations reduce membrane expression of glycosphingolipids in human cells (unpublished data). Glycosphingolipids include gangliosides and this would be consistent with disruption of ganglioside signalling within the CNS. GLT8D1 was recently identified as a risk gene for schizophrenia (Yang et al., 2018), and while schizophrenia is not a neurodegenerative disorder, it is noteworthy that ALS and schizophrenia share common genetic risk (McLaughlin et al., 2017).

UDP Glycosyltransferase 8 (UGT8)

Like GLT8D1, UGT8 is a member of glycosyltransferase family 8. UGT8 functions in the biosynthesis of galactocerebroside, a sphingolipid that forms the myelin membrane in the central and peripheral nervous systems. Rare and potentially pathogenic copy number variants have been identified in the promotor region of UGT8 following in an unbiased genome-wide screen for de novo DNA mutations in 12 trios including sporadic ALS patients and unaffected parents (Pamphlett et al., 2011). Abnormal lipid biosynthesis and metabolism is a pathological hallmark of ALS (Dupuis et al., 2008; Dorst et al., 2011), therefore it is possible that UGT8 plays a role in the hypolipidaemia observed in ALS patients and the SOD1-G93A ALS mouse model (Kim et al., 2011; Yang et al., 2013). Mice lacking Ugt8a, the orthologue of UGT8, exhibit impaired locomotor activity and disruption in nerve conduction followed by degeneration of the myelin sheath (Bosio et al., 1996; Coetzee et al., 1996), which is rescued following transgenic expression of UGT8A (Zoller et al., 2005). Interestingly the rescue occurred with expression of UGT8A under a promoter exclusively expressed within oligodendrocytes, which is consistent with other evidence implicating these cells in ALS-associated neurodegeneration (Morrison et al., 2013).

ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1)

ST6GAL1 is an 'inverting' enzyme and a member of glycosyltransferase family 29. ST6GAL1 catalyses the transfer of sialic acid onto galactose-containing substrates including cell-surface signalling lipids and proteins (Garnham et al., 2019). A genome-wide association study implicated polymorphisms within ST6GAL1 in the conversion of mild cognitive impairment into clinical Alzheimer's disease (Lee et al., 2017). Interestingly ST6GAL1 is cleaved and occurs in a soluble form; this cleavage is mediated by BACE1 (Kitazume et al., 2001), which is also involved in the cleavage of APP to form amyloid-β. Indeed, overexpression of ST6GAL1 increases APP secretion (Nakagawa et al., 2006) suggesting that the activity of ST6GAL1 can directly modify the central pathway in the development of Alzheimer's pathology.

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