Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?

Abstract

Gangliosides are molecules widely present in the plasma membranes of mammalian cells, participating in a variety of processes, including protein organization, transmembrane signalling and cell adhesion. Gangliosides are abundant in the grey matter of the brain, where they are critically involved in postnatal neural development and function. The common precursor of the majority of brain gangliosides, GM3, is formed by the sialylation of lactosylceramide, and four derivatives of its a- and b-series, GM1, GD1a, GD1b and GT1b, constitute 95% of all the brain gangliosides. Impairments in ganglioside metabolism due to genetic abnormalities of GM-synthases are associated with severe neurological disorders. Apart from that, the latest genome-wide association and translational studies suggest a role of genes involved in brain ganglioside synthesis in less pervasive psychiatric disorders. Remarkably, the most recent animal studies showed that abnormal ganglioside functions result in dysregulated neuroinflammation, aberrant myelination and altered insulin receptor signalling. At the same time, these molecular features are well established as accompanying developmental psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). This led us to hypothesize a role of deficient ganglioside function in developmental neuropsychiatric disorders and warrants further gene association clinical studies addressing this question. Here, we critically review the literature to discuss this hypothesis and focus on the recent studies on ST3GAL5-deficient mice. In addition, we elaborate on the therapeutic potential of various anti-inflammatory remedies for treatment of developmental neuropsychiatric conditions related to aberrant ganglioside functions.

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

“…Recently, Tph2 +/− mice exposed to predator stress were shown to display excessive aggression, increased anxiety-like behaviours, and altered sociability and compromised brain metabolism of dopamine and noradrenaline [ 95 , 96 ]. The predation stress procedure elicited behavioural and molecular changes in Tph2 +/− mice that were the opposite of those observed in control mice [ 73 , 95 ].…”

“…In contrast to what was thought earlier, it is now established that myelination is not a single developmental event but rather a constant process of de novo formation of myelin in the nervous system [ 196 ]. Remodelling of the myelin sheaths, which was shown to be dependent on neural activity, is now thought to be involved in learning and long-term neuroplasticity [ 197 ] and the stress response [ 93 , 96 ]. For example, it was shown that in mice, fear learning induces oligodendrocyte precursor cell (OPC) proliferation and differentiation into myelinating oligodendrocytes in the medial PFC, whereas in transgenic mice with conditional deletion of Myrf transcription factor in OPCs, which prevents OPC maturation and expression of myelin structural genes while preserving existing myelin sheaths, long-term fear memory retrieval is impaired [ 198 ].…”

Disordered testosterone transport in mice lacking the ganglioside GM2/GD2 synthase gene

“…The enzyme activities of the mutated B4GALNT1 gene and patients' profiles were previously reported by our group [ 40 ]. The onset of abnormal signs and symptoms is generally later than those observed in patients with ST3GALT5 gene deficiency [ 15 , 16 , 17 , 18 ]. These findings in the B4GALNT1 mutation cases correspond well with abnormal phenotypes observed in the B4galnt1 KO mice [ 24 , 26 ].…”

“…Following progress in the generation and analysis of gene KO mice lacking certain glycosphingolipids, clinical cases due to deficient ganglioside synthase genes were reported, for example, GM3 synthase deficiency [ 15 , 16 , 17 , 18 ] and GM2/GD2 synthase deficiency [ 19 , 20 , 21 , 22 , 23 ]. Clinical information about these patients reflects the various “unexpected phenotypes” that the individual KO mice exhibited.…”