Synaptic metabolism and brain circuitries in inborn errors of metabolism

Abstract

Abbreviations IEM inborn errors of metabolismMore than 300 new inborn errors or metabolism (IEM) have been described during the last 5 years and most of them have major neurological symptoms (Ferreira et al. 2018;Saudubray and Garcia-Cazorla 2018). These disorders have changed paradigms transforming the concept and classification of IEM and are contributing enormously to our understanding of mechanisms in neurological diseases. A pioneer initiative in this direction was the description of the vast new group of complex lipid synthesis and remodelling defects that stands at the frontier between classical IEM and cellular neurobiology (Lamari et al. 2015). More recently, many defects affecting systems involved in intracellular vesiculation, trafficking, processing and quality control of complex molecules, such as protein folding and autophagy (Ebrahimi-Fakhari et al. 2016), have described a number of diseases with important repercussion in the brain.The -omics era is currently transforming neurology, and in particular child neurology, with the description of an increasing amount of new monogenic diseases. However, the pathophysiological approach to these disorders is mostly based on neuroanatomy, neurophysiology and the description of individual proteins. The role of metabolism, which strongly orchestrates neuronal function, has been mostly neglected in the study of brain disorders. On the other hand, the description of biological mechanisms of disease in the field of IEM has not fully considered the particularities of the nervous system. The human brain is a unique system that exhibits a complex architecture and a great diversity of functions and cellular types. Neurons are large and highly polarised cells consisting of axons and dendritic arborisations that communicate with each other through synaptic contacts, which are essential to their function. To integrate information within and between compartments, neurons need sophisticated transfer mechanisms, ensuring that necessary molecules are available in the right place at the right time. Metabolism is regulating these functions and appears to have specific properties at every single neuronal compartment. Metabolism has also specific rules depending on the specific subtype of nervous cell (different populations of neurons, glia, oligodendrocytes, microglia…). An important model of compartmentalised signalling and metabolism occurs at the synapse, which is the main topic of this special issue.The synapse is a highly specialised cell junction that connects a presynaptic transmitting neuron with a postsynaptic receiving neuron. Synapses connect more than one hundred billion neurons present in the human brain, and wire-select neurons into functional circuits, enabling the brain to process and transfer information (Südhof 2013). The concept of Bsynaptic metabolism^is introduced in this special issue and is the conducting wire of most of its articles; it could be defined as the specific chemical composition and metabolic functions occurring at the synapse. The presynapti...

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

“…This is because these small molecules contribute to antenatal brain "construction" in terms of signaling, cytoskeleton guidance, synapse formation and later on in experience-dependent synapse remodeling. 12 Interestingly, late-onset forms present as neurodegenerative disorders, reflecting the different roles of metabolism as the brain ages.…”

“…The concept of « synaptic metabolism » has been recently introduced and could be defined as the specific chemical composition and metabolic functions occurring at the synapse. 12 The synaptic vesicle (SV) is an independent complex and specialized organelle. Vesicular glycolysis was recently discovered to be capable of providing a constant intrinsic source of energy, independent of mitochondria, for the rapid axonal movement of vesicles over long distances.…”

“…For instance, mutations in genes coding for tubulin subunits ( TUBA1A , TUBB2B , TUBG1 ) and molecular motor proteins ( KIF2A , KIF5C , DYNC1H1 ) can produce cortical migration defects and lead to severe complex encephalopathies in a similar way than AA synthesis defects. This is because these small molecules contribute to antenatal brain “construction” in terms of signaling, cytoskeleton guidance, synapse formation and later on in experience‐dependent synapse remodeling . Interestingly, late‐onset forms present as neurodegenerative disorders, reflecting the different roles of metabolism as the brain ages.…”

Free virtual issue: Novel paradigms for inborn errors with muscular and central neuropathology

“…Molecular technologies, for example, whole‐exome sequencing, have rapidly accelerated Mendelian disease discovery. In the last decade, several hundred inborn errors of metabolism have been discovered 1 . Most of these disorders show significant central nervous system involvement.…”

Free virtual issue: novel paradigms for in inborn errors with muscular and central neuropathology

“…Molecular technologies, for example whole‐exome sequencing (WES), have rapidly accelerated Mendelian disease discovery. In the last decade, several hundred inborn errors of metabolism have been discovered [1]. Most of these disorders show significant central nervous system involvement.…”