Abstract
Protein ubiquitination belongs to the best characterized pathways of protein degradation in the cell; however, our current knowledge on its physiological consequences is just the tip of an iceberg. The divergence of enzymatic executors of ubiquitination led to some 600–700 E3 ubiquitin ligases embedded in the human genome. Notably, mutations in around 13% of these genes are causative of severe neurological diseases. Despite this, molecular and cellular context of ubiquitination remains poorly characterized, especially in the developing brain. In this review article, we summarize recent findings on brain-expressed HECT-type E3 UBE3 ligases and their murine orthologues, comprising Angelman syndrome UBE3A, Kaufman oculocerebrofacial syndrome UBE3B and autism spectrum disorder-associated UBE3C. We summarize evolutionary emergence of three UBE3 genes, the biochemistry of UBE3 enzymes, their biology and clinical relevance in brain disorders. Particularly, we highlight that uninterrupted action of UBE3 ligases is a sine qua non for cortical circuit assembly and higher cognitive functions of the neocortex.
Highlights
Among these are the brain expressed UBE3 enzymes: the founder of the subclass Ubiquitin Ligase E3A (UBE3A), with its gene loss-of-function resulting in Angelman syndrome (AS) and Ubiquitin Ligase E3B (UBE3B), linked to Kaufman oculocerebrofacial syndrome (KOS) as well as autism spectrum disorders (ASD)-associated Ubiquitin Ligase E3C
Loss of Ube3a leads to ineffective long-term potentiation (LTP) in the hippocampus, indicative of defects in neuronal circuitry associated with learning and memory [48]
There seems to be no requirement of the developmental window for UBE3A reinstatement for the restoration of hippocampal LTP [84], or excitation/inhibition balance identified in mouse prefrontal cortex in AS mouse model [85]
Summary
Uninterrupted communication between executive brain centers, on a molecular and single neuron level manifested as circuit activity, allows for integration of external and internal sensory stimuli and generation of appropriate efferent responses. Of a neuronal circuits in the mammalian neocortex starts during early neurogenesis, where at the ventricular zone (VZ) of the neural tube, radial glial cells (RGCs), give rise to postmitotic cells that differentiate into glutamatergic excitatory neurons. Cells 2020, 9, 2455 cortical neuron development is that the immature nerve cells born close to the VZ do not stay in situ but migrate radially to distribute horizontally into their target niches to establish neocortical layers. These cortical niches contain neurons originating from spatiotemporally defined RGC populations. On a circuit physiology level, these processes are thought to be supported by neocortical desynchronization of alpha/beta rhythm and synchronization of hippocampal theta/gamma oscillations [6,7]
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