Setting the stage for a role of the postsynaptic proteome in inherited neurometabolic disorders

Synapses are pivotal in cognition and behaviour, as they decode and store sensorial information. For this reason, they are very often involved in the pathophysiology of mental disorders. Synapses are typically divided in three compartments: the presynaptic button, the synaptic cleft and the postsynaptic element. The postsynaptic element of glutamatergic synapses, which represent the vast majority of central nervous system synapses (Beaulieu and Colonnier 1985; von Bohlen Und Halbach 2009; Defelipe et al. 2002), has a unique morphology, which is essential to its function. This structure was first described by Santiago Ramón y Cajal who named it ‘dendritic spine’ (Yuste 2015). Dendritic spines are dynamic protrusions of the postsynaptic membrane that present a bulbous head connected to the dendritic shaft through a thin neck (von Bohlen Und Halbach 2009). Another characteristic feature of dendritic spines is the presence of a very large protein complex beneath the postsynaptic membrane, the postsynaptic density (PSD). Recent large-scale proteomics experiments have produced a very detailed catalogue of the proteins which are present at the PSD, identifying hundreds of different proteins (Bayés and Grant 2009; Bayés et al. 2012, 2017; Distler et al. 2014; Focking et al. 2016; Roy et al. 2018). Paramount among PSD proteins are neurotransmitter receptors, which mediate the propagation of the incoming action potentials. Nevertheless, the PSD contains many other protein types, which participate in the translation of the electrical input into chemical signals, which ultimately drive the functional state of the synapse (Boeckers 2006; Kim and Sheng 2009; Sheng and Kim 2011; Dosemeci et al. 2016).

Neurotransmitter disorders are a group of inherited neurometabolic syndromes that are primarily caused by an altered bioavailability of neurotransmitter at the synapse (Pearl et al. 2007; Hoffman and Blau 2014; Marecos et al. 2014; Ng et al. 2015; Cortès-Saladelafont et al. 2016). They are generally caused by pathogenic mutations in genes expressed at the axon terminal. These code for enzymes involved in the synthesis or degradation of neurotransmitters. Nevertheless, genes coding for proteins responsible for neurotransmitter release and reuptake have also been reported mutated in these conditions. The presynaptic space has thus an important role in neurometabolic disorders. Pathophysiological descriptions of neuronal dysfunction in many other classic inborn errors of metabolism (intoxication disorders, energy defects and complex molecule defects) have been mainly described from a presynaptic perspective. This circumstance is in strong contrast with our understanding of the postsynaptic role in neurometabolic disorders. In this article, I explore what is known about the main metabolic pathways functioning at the postsynapse and their potential relevance in the field of neurometabolic disorders.

A close inspection to the postsynaptic proteome should readily inform us about the key metabolic pathways operating in it. To achieve this purpose, I have looked for molecular pathways in a reference PSD proteome (Bayés et al. 2017) using the information contained in the ‘Reactome Pathways Database’ (Fabregat et al. 2018). The bioinformatics analysis tools provided by ‘Panther Classification System’ (Mi et al. 2016) have been used to identify metabolic pathways significantly enriched in the PSD, as previously reported (Bayés et al. 2012; Reig-Viader et al. 2018). If a pathway is significantly enriched in the PSD, it means that it presents a higher number of components than would be expected by chance. The vast majority of pathways that have been identified in this exercise are intracellular signal transduction pathways (see Supplementary Table 1), which is in accordance with our current knowledge of the molecular characteristics of the postsynaptic proteome (Boeckers 2006; Kim and Sheng 2009; Sheng and Kim 2011; Bayés et al. 2012; Dosemeci et al. 2016). These pathways typically involve the activation of membrane receptors, G-proteins or small GTPases that result in a series of molecular events, mostly phosphorylation cascades, which ultimately promote changes in cellular physiology. Nevertheless, a number of canonical metabolic pathways could be identified in the postsynaptic machinery. These are primarily related to the energetic and protein metabolisms (Table 1). However, if one considers the expanded definition of inborn errors of metabolism (IEM), in which dysfunctions of protein traffic are also regarded as metabolic conditions (García-Cazorla and Saudubray, this issue), the list of postsynaptic metabolic pathways is extended (Table 1 and Fig. 1). Interestingly, this analysis also revealed that while the presynaptic button presents a set of specific metabolic pathways, the postsynaptic element does not seem to contain a similarly unique metabolism. With the exception of a pathway involved in the trafficking of α-amino-3-hydroxy-5-methyl-4-isoazolepropionic (AMPA) glutamate receptors, postsynaptic metabolic pathways underlay basic cellular functions. This is relevant, as it means that proteins involved in these processes are not unique to the postsynapse and thus a direct link between a mutation and a postsynaptic role in disease would not be straightforward.

As previously introduced, neurometabolic disorders are intimately associated with presynaptic physiology. The notion of postsynaptic metabolic disorders is, at this point, rather speculative, with hardly any scientific literature supporting it. It is plausible that neurotransmitter diseases will secondarily alter postsynaptic physiology. Actually, this has already been reported for the creatine transporter deficiency, which results in increased synaptic levels of creatine and a prolonged stimulation of GABA receptors, to which the postsynaptic neuron responds by reducing the number of inhibitory synapses (Salomons et al. 2003). Similar pathophysiological mechanisms have been shown for the SSADHD deficiency (Pearl et al. 2009; Reis et al. 2012). Nevertheless, in this section, I wish to explore if there is evidence suggesting that primary dysfunction of the postsynaptic metabolic pathways described above could be involved in neurological conditions. To achieve this goal, we have looked for those genes coding for proteins involved in postsynaptic metabolic pathways that when mutated cause inherited brain conditions. It is important to keep in mind that most postsynaptic metabolic pathways are not exclusive to the postsynapse. Thus, their mutation will not necessarily imply a clinically relevant affectation of the postsynaptic physiology.

In the recently developed field of synaptopathies (Brose et al. 2010; Grant 2012), the role of many postsynaptic proteins in mental disorders is already well established (Guilmatre et al. 2009; Hamdan et al. 2011; Kirov et al. 2011). Nevertheless, the vast majority of postsynaptic proteins known to cause brain conditions are not involved in metabolism. In this article, I have explored the possibility of a primary role in disease of postsynaptic proteins involved in metabolic pathways. I have shown that energy production, protein turnover and neurotransmitter receptor traffic are the major metabolic pathways present at the postsynapse and that many proteins from these processes cause inherited disorders encompassing neurological manifestations. Importantly, the most common neurological phenotypes caused by these disorders are intellectual disability and seizures. Although, many other symptoms are present, including movement disorders, as recently reported (Kurian M, this issue). The fact that intellectual disability and seizures are key phenotypes of well-established synaptopathies caused by postsynaptic proteins and of conditions caused by postsynaptic proteins involved in metabolism is suggestive of a role of postsynaptic metabolism in certain neurological conditions. Future research will be required to explore this hypothesis.