Dataset Information

Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders.

ABSTRACT: Homeostatic maintenance of physiological functions is fundamental to organismal well-being. Disruption or imbalance in homeostasis results in functional disturbances at molecular, cellular, and tissue levels, leading to manifestation as physical and mental illnesses. Homeostatic imbalance is caused by a range of pathophysiological mechanisms, including disrupted reduction-oxidation reactions, inflammatory responses, metabolic disturbances, or failure in quality control of cellular proteins and organelles. However, the roles for the protein/organelle quality control in the regulation of behaviors, in particular of cognitive processes, had not been well documented, until recent reports finally supported this concept. The frontline studies in neuroscience have revealed that synaptic components (e.g., synaptic proteins, organelles, neurotransmitters and their receptors) are selectively degraded by autophagy, a cellular recycling machinery implicated in surveillance and quality control of proteins and organelles responsible for the maintenance of cellular homeostasis. Apart from the canonical role of autophagy in supporting cell viability, synaptic autophagy appears to regulate synapse remodeling and plasticity. Consistently, emerging evidence suggests novel roles of autophagy in memory encoding, information processing, or cognitive functions. In this review, we overview recent progress in understanding the roles of neuronal autophagy in homeostatic maintenance of synaptic functions, with particular focus on how disruptions in these processes may contribute to the pathophysiology of psychiatric disorders.

SUBMITTER: Tomoda T

PROVIDER: S-EPMC6986983 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified SOD1 (superoxide dismutase 1), an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased MTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point toward an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and MTOR-dependent autophagy.Abbreviations: APO: apocynin; ATG: autophagy related; BAF: bafilomycin A1; BSO: buthionine sulfoximine; CV: coefficient of variation; DIV: days in vitro; H4K16ac: histone 4 lysine 16 acetylation; iPSC: induced-pluripotent stem cell; KANSL1: KAT8 regulatory NSL complex subunit 1; KdVS: Koolen-de Vries Syndrome; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEA: micro-electrode array; MTOR: mechanistic target of rapamycin kinase; NSL complex: nonspecific lethal complex; 8-oxo-dG: 8-hydroxydesoxyguanosine; RAP: rapamycin; ROS: reactive oxygen species; sEPSCs: spontaneous excitatory postsynaptic currents; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; SYN: synapsin; WRT: wortmannin.

Dataset Information

Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets