Presynaptic disorders: a clinical and pathophysiological approach focused on the synaptic vesicle

Abstract

The aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis-endocytosis cycle, with the main purpose of neurotransmitter release). Given that SVs have been defined as individual organelles, we highlight the link between the biological processes disturbed by genetic mutations and the clinical presentation of these disorders. The great majority of diseases may present as epileptic encephalopathies, intellectual disability (syndromic or nonsyndromic) with/without autism spectrum disorder (and other neuropsychiatric symptoms), and movement disorders. These symptoms may overlap and present in patients as a combination of clinical signs that results in the spectrum of the synaptopathies. A small number of diseases may also exhibit neuromuscular signs. In general, SV disorders tend to be severe, early encephalopathies that interfere with neurodevelopment. As a consequence, developmental delay and intellectual disability are constant in almost all the defects described. Considering that some of these diseases might mimic other neurometabolic conditions (and in particular treatable disorders), an initial extensive metabolic workup should always be considered. Further knowledge into pathophysiological mechanisms and biomarkers, as well as descriptions of new presynaptic disorders, will probably take place in the near future.

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

“…69 Mutations coding for many different proteins that regulate the SV exocytic-endocytic pathway have been described as responsible of a variety of disorders that share general characteristics of complex molecule disorders. 70,71 In particular, trafficking, intracellular vesiculation, chaperon proteins (folding, unfolding and disaggregation), protein-protein, protein-lipid, and lipid-lipid interaction compose the main mechanisms of this group of diseases. 71 Aminoacyl tRNA synthetases deficiencies compose a group of already more than 30 disorders With the exception of GARS and KARS, mitochondrial and cytoplasmic aaRSs are encoded by distinct nuclear genes.…”

“…70,71 In particular, trafficking, intracellular vesiculation, chaperon proteins (folding, unfolding and disaggregation), protein-protein, protein-lipid, and lipid-lipid interaction compose the main mechanisms of this group of diseases. 71 Aminoacyl tRNA synthetases deficiencies compose a group of already more than 30 disorders With the exception of GARS and KARS, mitochondrial and cytoplasmic aaRSs are encoded by distinct nuclear genes. 72,73 Aminoacyl-tRNA synthetases deficiencies present with a broad clinical spectrum with many neurological phenotypes.…”

Synaptic metabolism and brain circuitries in inborn errors of metabolism

“…The presynaptic and postsynaptic terminals have specific patterns of proteins and lipids; and even within each of these compartments, there are specialised areas. As an example, the active zone, a specialised region for neurotransmitter release at the presynaptic plasma membrane has a unique protein and lipid composition compared to other areas of the neuronal membrane (Cortès-Saladelafont et al 2018;Mochel 2018). The same is true for the postsynaptic density, characteristic of the postsynaptic element of excitatory synapses (Bayés and Grant 2009).…”

“…Additionally, the synaptic vesicle (SV) cycle, crucial to neurotransmission, is a complex mechanism involving many different elements: the structure and composition of the SV itself, exocytic and endocytic processes and interactions between proteins and lipids among other biological functions. Since the SV is an independent organelle, such as mitochondria and lysosomes, diseases of the synaptic vesicle may encompass a category of disorders itself (Cortès-Saladelafont et al 2018). These diseases present with the constant features, including neurodevelopmental delay or intellectual disability, and a spectrum of signs comprising epilepsy, behavioural problems and movement disorders.…”

Presynaptic development is controlled by the core active zone proteins CAST/ELKS

“…Many of these proteins are expressed as multiple isoforms with different regulatory domains that vary between different neuronal populations and stages of synapse development during neuronal circuit maturation (Ackermann et al 2015). It is emerging that many neurological disorders are caused by alterations in neurodevelopment (Willsey et al 2018) and mutations in presynaptic proteins can lead to neurological disorders (Cortes-Saladelafont et al 2018). Therefore, it is important to understand how presynaptic AZ proteins regulate synapse maturation during neuronal circuit development.…”