A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility.

Intellectual Disability is a common and heterogeneous disorder characterized by limitations in intellectual functioning and adaptive behaviour, whose molecular mechanisms remain largely unknown. Among the numerous genes found to be involved in the pathogenesis of intellectual disability, 10% are located on the X-chromosome. We identified a missense mutation (c.236 C > G; p.S79W) in the SYN1 gene coding for synapsin I in the MRX50 family, affected by non-syndromic X-linked intellectual disability. Synapsin I is a neuronal phosphoprotein involved in the regulation of neurotransmitter release and neuronal development. Several mutations in SYN1 have been identified in patients affected by epilepsy and/or autism. The S79W mutation segregates with the disease in the MRX50 family and all affected members display intellectual disability as sole clinical manifestation. At the protein level, the S79W Synapsin I mutation is located in the region of the B-domain involved in recognition of highly curved membranes. Expression of human S79W Synapsin I in Syn1 knockout hippocampal neurons causes aberrant accumulation of small clear vesicles in the soma, increased clustering of synaptic vesicles at presynaptic terminals and increased frequency of excitatory spontaneous release events. In addition, the presence of S79W Synapsin I strongly reduces the mobility of synaptic vesicles, with possible implications for the regulation of neurotransmitter release and synaptic plasticity. These results implicate SYN1 in the pathogenesis of non-syndromic intellectual disability, showing that alterations of synaptic vesicle trafficking are one possible cause of this disease, and suggest that distinct mutations in SYN1 may lead to distinct brain pathologies.

MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis?

Although Rett syndrome (RTT) represents one of the most frequent forms of severe intellectual disability in females worldwide, we still have an inadequate knowledge of the many roles played by MeCP2 (whose mutations are responsible for most cases of RTT) and their relevance for RTT pathobiology. Several studies support a role of MeCP2 in the regulation of synaptic plasticity and homeostasis. At the molecular level, MeCP2 is described as a repressor capable of inhibiting gene transcription through chromatin compaction. Indeed, it interacts with several chromatin remodeling factors, such as HDAC-containing complexes and ATRX. Other studies have inferred that MeCP2 functions also as an activator; a role in regulating mRNA splicing and in modulating protein synthesis has also been proposed. Further, MeCP2 avidly binds both 5-methyl- and 5-hydroxymethyl-cytosine. Recent evidence suggests that it is the highly disorganized structure of MeCP2, together with its post-translational modifications (PTMs) that generate and regulate this functional versatility. Indeed, several reports have demonstrated that differential phosphorylation of MeCP2 is a key mechanism by which the methyl binding protein modulates its affinity for its partners, gene expression and cellular adaptations to stimuli and neuronal plasticity. As logic consequence, generation of phospho-defective Mecp2 knock-in mice has permitted associating alterations in neuronal morphology, circuit formation, and mouse behavioral phenotypes with specific phosphorylation events. MeCP2 undergoes various other PTMs, including acetylation, ubiquitination and sumoylation, whose functional roles remain largely unexplored. These results, together with the genome-wide distribution of MeCP2 and its capability to substitute histone H1, recall the complex regulation of histones and suggest the relevance of quickly gaining a deeper comprehension of MeCP2 PTMs, the respective writers and readers and the consequent functional outcomes.