The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

Shin, Woo Hyun; Park, Joon Hyung; Chung, Kwang Chul

doi:10.5483/bmbrep.2020.53.1.283

Cited by 69 publications

(44 citation statements)

References 76 publications

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“…Enhancement of Nrf2 activity may also result from blocking its binding to Keap1 by the autophagy adaptor protein p62, which channels Keap1 to degradation in autophagosomes. Proteasomal destruction of Nrf2 can also be inhibited via phosphorylation by several protein kinases, such as members of the Src family, by induction of transcription factors for the increased expression of Nrf2, or the downregulation of inhibitory microRNAs or of Keap1 expression [40,47,48] (Figure 2).…”

Section: Phenolic Phytochemicals In Coffee May Account For Health Effmentioning

confidence: 99%

Health Effects of Coffee: Mechanism Unraveled?

2020

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The association of habitual coffee consumption with a lower risk of diseases, like type 2 diabetes mellitus, chronic liver disease, certain cancer types, or with reduced all-cause mortality, has been confirmed in prospective cohort studies in many regions of the world. The molecular mechanism is still unresolved. The radical-scavenging and anti-inflammatory activity of coffee constituents is too weak to account for such effects. We argue here that coffee as a plant food has similar beneficial properties to many vegetables and fruits. Recent studies have identified a health promoting mechanism common to coffee, vegetables and fruits, i.e., the activation of an adaptive cellular response characterized by the upregulation of proteins involved in cell protection, notably antioxidant, detoxifying and repair enzymes. Key to this response is the activation of the Nrf2 (Nuclear factor erythroid 2-related factor-2) system by phenolic phytochemicals, which induces the expression of cell defense genes. Coffee plays a dominant role in that regard because it is the major dietary source of phenolic acids and polyphenols in the developed world. A possible supportive action may be the modulation of the gut microbiota by non-digested prebiotic constituents of coffee, but the available data are still scarce. We conclude that coffee employs similar pathways of promoting health as assumed for other vegetables and fruits. Coffee beans may be viewed as healthy vegetable food and a main supplier of dietary phenolic phytochemicals.

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Section: Phenolic Phytochemicals In Coffee May Account For Health Effmentioning

confidence: 99%

Health Effects of Coffee: Mechanism Unraveled?

2020

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“…This induces UPR, in which damaged proteins are targeted by chaperones, but if this fails, soluble proteins are ubiquitinated and degraded in the proteasome, and molecular chaperones may assist this process [ 129 ]. Aging and neurodegeneration may result in dys- or non-functional proteasomal system, leading to accumulation of ubiquitinated proteins, which in turn are targeted by autophagy receptors, including p62/SQSTM1 (sequestosome 1) and LC3 [ 130 ].…”

Section: Age-related Macular Degeneration—a Disease Of Aging Stresmentioning

confidence: 99%

The Aging Stress Response and Its Implication for AMD Pathogenesis

Błasiak

Pawłowska

Sobczuk

et al. 2020

IJMS

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Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

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“…Indeed, in an UPS-impaired Parkinson's mouse model, UPS inhibition activated the autophagy-lysosomal system in mDANs [ 540 ]. UPS and autophagy are closely related and dynamically interconnected, where p62/SQSTM1 appears to be one of the main modulators [ 541 – 543 ]. In addition, previous evidence indicates that proteasome function is modulated by redox modifications [ 544 ].…”

Section: Autophagy and Oxidative Stress In Parkinson'smentioning

confidence: 99%

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

Jiménez-Moreno

Lane

2020

Oxidative Medicine and Cellular Longevity

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson’s is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson’s. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson’s.

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The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

Cited by 69 publications

References 76 publications

Health Effects of Coffee: Mechanism Unraveled?

Health Effects of Coffee: Mechanism Unraveled?

The Aging Stress Response and Its Implication for AMD Pathogenesis

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

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