Conclusions and perspectives
The COG complex and its Rab and SNARE partners are evolutionarily conserved and ubiquitously expressed across multiple tissues and organ systems in humans. Yet, neurological symptoms are the most debilitating and troublesome clinical manifestations of COG-associated disorders. Why is this the case? We propose that brain-specific manifestations of COG defects result from either COG-dependent (a) glycosylation defects and/or, (b) trafficking defects and/or, (c) a yet unknown neuron/neuroglia-specific function of the COG complex and its partners.
Neuronal function critically depends on coordinated delivery of properly modified ion channels, transporters and components of the synaptic apparatus at the appropriate rates and over long distances, to specific subcellular compartments. Remarkably, the localization of the synaptobrevin homolog Snc1 is altered in COG deficient yeast cells (Whyte and Munro, 2002). In addition, underglycosylated low density lipoprotein receptor is severely destabilized in CHO cells deficient for COG1 or COG2 proteins (Kingsley et al., 1986). Since glycosylation of channels, transporters and transport regulators is essential for their correct delivery, stability and/or activity (Gong et al., 2002; Watanabe et al., 2004; Scott and Panin, 2014), it is reasonable to predict that a majority of underglycosylated ion channels and transporters may similarly be destabilized, thus altering the functionality of COG-CDG patient neurons.
Smooth transport of cargo by the trafficking machinery is very important during development and synaptic transmission. Defective glycosylation of proteins and lipids disrupts development pathways and alters brain function (Freeze et al., 2012). COG deficient cells also display altered glycosphingolipid biosynthesis. Complex gangliosides are sialic acid containing glycosphingolipids synthesized sequentially, beginning with GM3 and then extended by glycosyltransferases to the more elaborate GM1 gangliosides. Biochemical studies revealed decreased levels of sphingomyelin and GM3 gangliosides in COG2 deficient CHO cells (Spessott et al., 2010a,b). Gangliosides are ubiquitously expressed, but in the brain the expression of gangliosides and their glycosyltransferases change dramatically during development, from an abundance in of the precursor GM3 to a greater abundance of GM1 (Yu et al., 1988; Kracun et al., 1991, 1992; Ngamukote et al., 2007). Therefore, altered glycosphingolipid biosynthesis could be another reason for the specific neurological manifestation in COG-related congenital disorders.
An additional factor that may add to the apparently higher neuronal vulnerability to COG deficiency is that unlike many other cells, neurons are non-dividing cells and hence cannot easily dilute toxic proteins, peptides, and organelles. Another possibility is that COG is playing a specific and yet uncovered role in neuronal cells. Although the COG complex has been largely detected at the established perinuclear Golgi location in neurons (Figure 1) this does not exclude some sort of moonlighting function for COG subunits at other neuron-specific locations where it could be involved in tethering of specialized vesicles.
Considering the systemic and complex character of COG-related diseases, multiple questions regarding the associated neurological symptoms remain to be addressed. Thus, more in vivo studies are needed to dissect the role of COG and its Rab and SNARE partners in these symptoms. Input from COG deficiencies within neuroglia and subtypes of neuroglia presents yet another poorly studied field and avenue requiring further studies. Further research is also needed to establish in which diseases COG-deficiency-associated neurological syndromes are secondary manifestations of some other primary disease state.

Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.