O-GlcNAcylation is a posttranslational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of many proteins. This protein modification interacts with key cellular pathways involved in transcription, translation, and proteostasis. Although ubiquitous throughout the body, O-GlcNAc is particularly abundant in the brain, and various proteins commonly found at synapses are O-GlcNAcylated. Recent studies have demonstrated that the modulation of O-GlcNAc in the brain alters synaptic and neuronal functions. Furthermore, altered brain O-GlcNAcylation is associated with either the etiology or pathology of numerous neurodegenerative diseases, while the manipulation of O-GlcNAc exerts neuroprotective effects against these diseases. Although the detailed molecular mechanisms underlying the functional roles of O-GlcNAcylation in the brain remain unclear, O-GlcNAcylation is critical for regulating diverse neural functions, and its levels change during normal and pathological aging. In this review, we will highlight the functional importance of O-GlcNAcylation in the brain and neurodegenerative diseases.
See Hart and Huang (doi: ) for a scientific commentary on this article. Lee et al. show that O-GlcNAcylation, an evolutionarily conserved post-translational modification, is critical for the physiological functioning and survival of dopaminergic neurons. Upregulating O-GlcNAcylation mitigates neurodegeneration, synaptic impairments and motor deficits in a mouse model of Parkinson’s disease.
Generation of autologous human motor neurons holds great promise for cell replacement therapy to treat spinal cord injury (SCI). Direct conversion allows generation of target cells from somatic cells, however, current protocols are not practicable for therapeutic purposes since converted cells are post-mitotic that are not scalable. Therefore, therapeutic effects of directly converted neurons have not been elucidated yet. Here, we show that human fibroblasts can be converted into induced motor neurons (iMNs) by sequentially inducing POU5F1(OCT4) and LHX3. Our strategy enables scalable production of pure iMNs because of the transient acquisition of proliferative iMN-intermediate cell stage which is distinct from neural progenitors. iMNs exhibited hallmarks of spinal motor neurons including transcriptional profiles, electrophysiological property, synaptic activity, and neuromuscular junction formation. Remarkably, transplantation of iMNs showed therapeutic effects, promoting locomotor functional recovery in rodent SCI model. Together, our advanced strategy will provide tools to acquire sufficient human iMNs that may represent a promising cell source for personalized cell therapy.
Dopaminergic axons originate in the midbrain and establish widely spread synapses throughout the brain. Synaptic transmission at these synapses plays a crucial role for volitional movement and reward-related behaviors, while dysfunction of dopamine (DA) synapses causes various psychiatric and neurological disorders. Despite this significance, the true nature of brain-wide spatial and functional features of DA synapses remains poorly understood due to difficulties defining functional DA synapses at the molecular and physiological levels. Here we show that DA synapses are structured and function like GABAergic synapses in the mouse brain with marked regional heterogeneity. DA transmission is strongly correlated with GABA co-transmission at DA synapses across the brain areas. In addition, functional DA synapses possess GABAergic postsynaptic markers and are unevenly distributed throughout the brain with distinct spatial clustering. In the dorsal striatum, GABAergic-like DA synapses are uniquely clustered on the dendrites and GABA transmission at DA synapses has disparate physiological properties. Remarkably, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission in animal model of Parkinsonism. Our findings unravel distinct spatial and functional nature of GABAergic-like DA synapses in health and disease. Furthermore, the broader implication of our results is that GABAergic-like features of DA synapses can be utilized to better understand the real complexity of synaptic actions at DA synapses in regulating neural circuits.
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