The Relationship Between Autophagy and Brain Plasticity in Neurological Diseases

Wang, Manman; Feng, Ya-Shuo; Yang, Sidong; Xing, Ying; Zhang, Jing; Dong, Fang; Zhang, Feng

doi:10.3389/fncel.2019.00228

Cited by 24 publications

(15 citation statements)

References 79 publications

(87 reference statements)

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“…This observation may be partially due to the presence of antipsychotic drugs (e.g., olanzapine and pimozide) and liver disease drugs (e.g., carbamazepine and resveratrol) in our input list of autophagy modulators, both developed for eliminating toxic aggregates. However, it also reflects the crucial role of autophagy in liver and brain health and diseases [111][112][113] and justifies the attempts of repurposing autophagy modulators against liver and brain diseases [21][22][23].…”

Section: Discussionmentioning

confidence: 91%

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi

Pei

Silverman

et al. 2020

IJMS

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Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

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Section: Discussionmentioning

confidence: 91%

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi

Pei

Silverman

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…carbamazepine and resveratrol) in our input list of autophagy modulators, both developed for eliminating toxic aggregates. However, it also reflects the crucial role of autophagy in liver and brain health and diseases [107][108][109] and justifies the attempts of repurposing autophagy modulators against liver and brain diseases [21][22][23]. The targets involved in cardiovascular diseases are mainly calcium channels.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi

Pei

Perlmutter

et al. 2020

Preprint

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Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g. artenimol and olanzapine acting as activator, fostamatinib as inhibitor, or melatonin as dual-modulator), as well as selected drugs uniquely targeting specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulates the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker bridging between various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

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“…Loss of autophagy in neurons causes defects in cargo-specific axonal transport, which lead to axon swelling and axonal dystrophy ( Komatsu et al ., 2006 ; Lee et al ., 2011 ) as well as over-formation of dendritic spine density due to deficits in synaptic pruning ( Tang et al ., 2014 ). Autophagosome biogenesis is observed near synapses ( Stavoe et al ., 2016 ), and autophagy is required for synapse development and neuronal plasticity ( Shen and Ganetzky, 2009 ; Wang et al ., 2019 ). Rapamycin-induced macroautophagy rapidly inhibits neurotransmitter release in dopaminergic neurons ( Hernandez et al ., 2012 ), and autophagy regulates presynaptic neurotransmission by controlling axonal ER calcium release in hippocampal neurons ( Kuijpers et al ., 2020 ).…”

Section: Role Of Autophagy In Neuronal Pathophysiologymentioning

confidence: 99%

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology

Valencia

Kim

Jang

et al. 2021

Biomol Ther (Seoul)

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Autophagy is an important degradative pathway that eliminates misfolded proteins and damaged organelles from cells. Autophagy is crucial for neuronal homeostasis and function. A lack of or deficiency in autophagy leads to the accumulation of protein aggregates, which are associated with several neurodegenerative diseases. Compared with non-neuronal cells, neurons exhibit rapid autophagic flux because damaged organelles or protein aggregates cannot be diluted in post-mitotic cells; because of this, these cells exhibit characteristic features of autophagy, such as compartment-specific autophagy, which depends on polarized structures and rapid autophagy flux. In addition, neurons exhibit compartment-specific autophagy, which depends on polarized structures. Neuronal autophagy may have additional physiological roles other than amino acid recycling. In this review, we focus on the characteristics and regulatory factors of neuronal autophagy. We also describe intracellular selective autophagy in neurons and its association with neurodegenerative diseases.

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The Relationship Between Autophagy and Brain Plasticity in Neurological Diseases

Cited by 24 publications

References 79 publications

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology

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