Autophagy and proteostasis in the control of synapse aging and disease

Liang, YongTian; Sigrist, Stephan J.

doi:10.1016/j.conb.2017.12.006

Cited by 60 publications

(60 citation statements)

References 73 publications

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“…In response to stress, autophagy pathways mediate the degradation of cellular components; organelles, as well as lipids and proteins, to generate nutrients and metabolic building blocks to maintain cellular homeostasis ( Dikic and Elazar, 2018 ; Ejlerskov et al, 2018 ). Autophagic processes in post-mitotic cells such as neurons, cardiac myocytes, and retinal pigment epithelium (RPE), are essential for cellular quality control, as these cells are unable to decrease their load of damaged organelles, accumulated lipids or protein aggregates through cell division ( Boya et al, 2016 ; Liang and Sigrist, 2018 ). During aging, autophagy is critical to remove damaged components that would otherwise accumulate and catalyze the formation of cytotoxic molecules in situ under oxidative stress ( Lee et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium

Dhingra

Bell

Peachey

et al. 2018

Front. Cell. Neurosci.

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Like other neurons, retinal cells utilize autophagic pathways to maintain cell homeostasis. The mammalian retina relies on heterophagy and selective autophagy to efficiently degrade and metabolize ingested lipids with disruption in autophagy associated degradation contributing to age related retinal disorders. The retinal pigment epithelium (RPE) supports photoreceptor cell renewal by daily phagocytosis of shed photoreceptor outer segments (OS). The daily ingestion of these lipid-rich OS imposes a constant degradative burden on these terminally differentiated cells. These cells rely on Microtubule-Associated Protein 1 Light Chain 3 (LC3) family of proteins for phagocytic clearance of the ingested OS. The LC3 family comprises of three highly homologous members, MAP1LC3A (LC3A), MAP1LC3B (LC3B), and MAP1LC3C (LC3C). The purpose of this study was to determine whether the LC3B isoform plays a specific role in maintaining RPE lipid homeostasis. We examined the RPE and retina of the LC3B-/- mouse as a function of age using in vivo ocular imaging and electroretinography coupled with ex vivo, lipidomic analyses of lipid mediators, assessment of bisretinoids as well as imaging of lipid aggregates. Deletion of LC3B resulted in defects within the RPE including increased phagosome accumulation, decreased fatty acid oxidation and a subsequent increase in RPE and sub-RPE lipid deposits. Age-dependent RPE changes included elevated levels of oxidized cholesterol, deposition of 4-HNE lipid peroxidation products, bisretinoid lipofuscin accumulation, and subretinal migration of microglia, collectively likely contributing to loss of retinal function. These observations are consistent with a critical role for LC3B-dependent processes in the maintenance of normal lipid homeostasis in the aging RPE, and suggest that LC3 isoform specific disruption in autophagic processes contribute to AMD-like pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium

Dhingra

Bell

Peachey

et al. 2018

Front. Cell. Neurosci.

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“…Autophagy not only regulates early neuronal development but also plays specific, multiple, and largely unexplored roles at synapses. As recently reviewed, dysfunctional autophagy at both pre-and post-synaptic sites leads to aging and neurodegeneration (Nikoletopoulou et al, 2015;Vijayan and Verstreken, 2017;Azarnia Tehran et al, 2018;Liang and Sigrist, 2018). Degradation of postsynaptic neurotransmitter receptors involves trafficking in autophagosomal structures (Rowland, 2006;Shehata et al, 2012Shehata et al, , 2018Hui et al, 2019).…”

Section: Autophagy and Synaptic Functionmentioning

confidence: 99%

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

Falace

Esposito

Aprile

et al. 2020

Front. Cell. Neurosci.

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Autophagy is a highly conserved degradative process that conveys dysfunctional proteins, lipids, and organelles to lysosomes for degradation. The post-mitotic nature, complex and highly polarized morphology, and high degree of specialization of neurons make an efficient autophagy essential for their homeostasis and survival. Dysfunctional autophagy occurs in aging and neurodegenerative diseases, and autophagy at synaptic sites seems to play a crucial role in neurodegeneration. Moreover, a role of autophagy is emerging for neural development, synaptogenesis, and the establishment of a correct connectivity. Thus, it is not surprising that defective autophagy has been demonstrated in a spectrum of neurodevelopmental disorders, often associated with early-onset epilepsy. Here, we discuss the multiple roles of autophagy in neurons and the recent experimental evidence linking neurodevelopmental disorders with epilepsy to genes coding for autophagic/lysosomal system-related proteins and envisage possible pathophysiological mechanisms ranging from synaptic dysfunction to neuronal death.

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“…The integrity of vertebrate synapses requires robust cellular programs that monitor the activity states of thousands of proteins, eliminating those that are misfolded or damaged. Failure of these programs can lead to the accumulation of nonfunctional proteins that reduce the efficiency of synaptic transmission and promote neurodegeneration (Waites et al, 2013;Vijayan and Verstreken, 2017;Liang and Sigrist, 2018). Neurons are endowed with several surveillance and clearance systems.…”

Section: Introductionmentioning

confidence: 99%

Light-Activated ROS Production Induces Synaptic Autophagy

et al. 2019

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The regulated turnover of synaptic vesicle (SV) proteins is thought to involve the ubiquitin-dependent tagging and degradation through endo-lysosomal and autophagy pathways. Yet, it remains unclear which of these pathways are used, when they become activated, and whether SVs are cleared en masse together with SV proteins or whether both are degraded selectively. Equally puzzling is how quickly these systems can be activated and whether they function in real-time to support synaptic health. To address these questions, we have developed an imaging-based system that simultaneously tags presynaptic proteins while monitoring autophagy. Moreover, by tagging SV proteins with a light-activated ROS generator, Supernova, it was possible to temporally control the damage to specific SV proteins and assess their consequence to autophagy-mediated clearance mechanisms and synaptic function. Our results show that, in mouse hippocampal neurons of either sex, presynaptic autophagy can be induced in as little as 5-10 min and eliminates primarily the damaged protein rather than the SV en masse. Importantly, we also find that autophagy is essential for synaptic function, as light-activated damage to, for example, Synaptophysin only compromises synaptic function when autophagy is simultaneously blocked. These data support the concept that presynaptic boutons have a robust highly regulated clearance system to maintain not only synapse integrity, but also synaptic function.

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Autophagy and proteostasis in the control of synapse aging and disease

Cited by 60 publications

References 73 publications

Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium

Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium

Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

Light-Activated ROS Production Induces Synaptic Autophagy

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