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

Impaired Ganglioside Synthesis is Linked to Neurodegeration

Parkinson's Disease

Reduced glycosyltransferase expression and lowered ganglioside synthesis has been implicated in the pathogenesis of Parkinson's disease. A recent report described a reduction in gene expression of the glycosyltransferases B3GALT4 and ST3GAL2 in neuromelanin-containing neurons in the substantia nigra of patients with Parkinson's disease compared to control subjects (Schneider, 2018). These genes are key players in the ganglioside biosynthesis pathway (Figure 1). It is proposed that reduced B3GALT4 and ST3GAL2 expression leads to vulnerability of dopaminergic neurons via aberrant ganglioside synthesis. Consistent with this hypothesis, the number of GM1 ganglioside-expressing cells in the Parkinson's disease substantia nigra are reduced (Wu et al., 2012), and levels of the major brain gangliosides—GM1, GD1a, GD1b and GT1b—are decreased in whole substantia nigra homogenates from patients with Parkinson's disease (Seyfried et al., 2018). Model systems provide evidence that dysfunction of ganglioside synthesis is a cause and not just an association of typical Parkinson's disease pathology: genetically engineered mice lacking major brain gangliosides display overt motor impairment with increasing age, which is accompanied by loss of dopaminergic neurons from the substantia nigra pars compacta and aggregation of α-synuclein (Wu et al., 2012).

Huntington's Disease

In a similar manner to Parkinson's disease, reduced expression of glycosyltransferases involved in ganglioside synthesis has also been described in the R6/1 mouse model of Huntington's disease and in human Huntington's disease patients (Desplats et al., 2007). In this study >80% of gene expression changes observed in the striatum of R6/1 mice were also observed in the post-mortem caudate of human Huntington's disease subjects. Overlapping genes were significantly enriched with glycosyltransferases involved in ganglioside synthesis including ST3GAL5, ST8SIA3, B4GALNT1 and ST3GAL2 (Figure 1). Consistent with impaired ganglioside synthesis, the same study reported reduced ganglioside concentrations within both the diseased human caudate and the mouse striatum. It should be noted that despite significant homology to ST8SIA1, which has a well described role in ganglioside biosynthesis (Figure 1), ST8SIA3 is traditionally associated with N-glycosylation of secreted/membrane proteins within the CNS (Lin et al., 2019). Like gangliosides, N-glycosylated proteins are important for cell signalling.

Alzheimer's Disease

There is good evidence for perturbed ganglioside metabolism in patients with Alzheimer's disease, and in the development of amyloid-β pathology in particular (Barrier et al., 2007). In contrast to the findings in Parkinson's disease and Huntington's disease, the key observation appears to be increased ganglioside synthesis. Elevated GM1, GM2 and GM3 levels have been reported in the cerebral cortices of Alzheimer's disease patients (Kracun et al., 1992; Gylys et al., 2007). Development of amyloid-β deposition is the defining pathology of Alzheimer's disease and within brains exhibiting early Alzheimer's disease pathology, a significant proportion of amyloid-β is bound to ganglioside species (Yanagisawa and Ihara, 1998). It has even been suggested that insoluble GM1-bound amyloid-β is the key toxin leading to neuronal death (Hayashi et al., 2004), as a result of high affinity binding between GM1 and amyloid-β, which facilitates formation of insoluble β-pleated sheets (Yamamoto et al., 2007). With increasing age GM1 is localized to presynaptic nerve terminals and this may have a role in directing amyloid-β deposition to the same locations (Yamamoto et al., 2008). Unlike evidence regarding gangliosides, reports of altered glycosyltransferase expression in Alzheimer's disease are more limited. There is evidence that glycosyltransferase activity may modify Alzheimer's disease pathology: overexpression of the glycosyltransferase B4GALNT1 leads to increased ganglioside expression but also increases APP cleavage to form amyloid-β pathology through suppression of lysosomal degradation of BACE1 (Yamaguchi et al., 2016). Currently, transgenic mouse models of Alzheimer's disease do not mirror changes in ganglioside distribution seen in human post-mortem tissue (Barrier et al., 2007).

Amyotrophic Lateral Sclerosis

ALS has been linked to abnormal lipid metabolism (Desport et al., 2005) and in particular, gangliosides and their ceramide precursors are thought to be modulators of disease progression (Salazargrueso et al., 1990; Stevens et al., 1993). Whether ganglioside production is increased or decreased is controversial. As early as 1985 a 10% reduction in b-series gangliosides was identified within the motor cortex of ALS brains compared to non-ALS controls (Rapport et al., 1985). More recently elevated levels of gangliosides GM1 and GM3 were reported within ALS post-mortem spinal cords compared to age-matched controls; findings were corroborated in the SOD1-G93A transgenic ALS mouse model (Dodge et al., 2015). Interestingly, autoantibodies against specific gangliosides produce an inflammatory disease of spinal motor neurons known as multifocal motor neuropathy with conduction block (Harschnitz et al., 2014), which is a frequent differential diagnosis of ALS.

ALS specifically inflicts pathology on the upper and lower motor neurons, the neuromuscular junction and muscle. The accessibility of this system in disease models facilitates the differentiation of up- and downstream disease associations. For example, increased expression of glycosphingolipids is observed in muscle tissue from end-stage mutant SOD1-ALS mice compared to controls, but similar changes were observed in response to surgically-induced muscle denervation suggesting a downstream effect (Henriques et al., 2015). Moreover, neurotransmission at the neuromuscular junction is unchanged in aged GM2 and GD3-deficient mice compared to controls (Zitman et al., 2011). However, our discovery that mutations in the glycosyltransferase GLT8D1 are a cause of familial ALS is a step forward, which places glycosyltransferase activity irrefutably upstream in the development of disease.

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