Brain metabolism as a modulator of autophagy in neurodegeneration

Lim, Yean Teng; Cho, Hanchae; Kim, Eun Kyoung

doi:10.1016/j.brainres.2016.02.049

Cited by 19 publications

(11 citation statements)

References 149 publications

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“…Because the UPR pathway inhibits NMD [60, 61, 75], it is likely (though not yet directly tested) that NMD is suppressed in neural cells from such patients. Suppressed NMD is known to cause apoptosis [74, 134] and, indeed, neurodegenerative disease is often accompanied by neuron loss [165]. By restoring high levels of NMD, NMD activator therapy has the potential to promote neuron survival.…”

Section: Perspectivesmentioning

confidence: 99%

“…By restoring high levels of NMD, NMD activator therapy has the potential to promote neuron survival. Neurodegenerative disease is also commonly accompanied by autophagy dysregulation [165], which may have a role in the formation of potentially toxic aggregates—such as amyloid plaques, tau tangles, and Lewy bodies—which are often present in diseased neurons [165]. One approach to deplete such bodies is NMD inhibitory therapy, as this treatment would be predicted to stimulate autophagy [117].…”

Section: Perspectivesmentioning

confidence: 99%

“…One approach to deplete such bodies is NMD inhibitory therapy, as this treatment would be predicted to stimulate autophagy [117]. Conversely, NMD activator therapy could provide clinical benefit for neural diseases in which autophagy is abnormally elevated [165]. Signaling pathways are also known to be dysregulated in several neurodegenerative diseases [166–168], which is interesting in light of the recent work demonstrating that the NMD pathway regulates TGF-β signaling and possibly Wnt and Notch signaling [28, 29].…”

Section: Perspectivesmentioning

confidence: 99%

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Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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Cells respond to internal and external cellular stressors by activating stress response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly-conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—Nonsense-Mediated RNA Decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses.

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Section: Perspectivesmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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“…Recent studies have demonstrated that Aβ is closely related to autophagy [ 49 ]. Autophagy is essential for maintaining cellular metabolism homeostasis and, as a sweeper for toxic materials such as Aβ, which has provided a new perspective on the pathophysiology of neurodegenerative diseases [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of ovarian hormone loss on neuritic plaques and autophagic flux in the brains of adult female APP/PS1 double-transgenic mice

Yao¹,

Feng²,

Yang³

et al. 2018

ABBS

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Epidemiologic studies have demonstrated that women account for two-thirds of Alzheimer’s disease (AD) cases, for which the decline in circulating gonadal hormone is considered to be one of the major risk factors. In addition, ovarian hormone deficiency may affect β-amyloid (Aβ) deposition, which has a close relationship with autophagic flux. In this study, we investigated the impact of short-term or long-term ovarian hormone deprivation on two mouse models, the non-transgenic (wild-type) and the APP/PS1 double-transgenic AD (2×TgAD) model. Autophagy-related proteins (Beclin1, LC3, and p62) and lysosome-related proteins were detected to evaluate Aβ deposition and autophagy. Our results showed that in the group with short-term depletion of ovarian hormones by ovariectomy (ovx), Beclin1, Cathepsin B (Cath-B), and LAMP1 levels were significantly decreased, while the levels of LC3-II and p62 were increased. In the long-term group, however, there was a sharp decline in Beclin1, LC3-II, Cath-B, and LAMP1 expression but not in p62 expression which is increased. It is worthwhile to note that the occurrence of neuritic plaque-induced ovarian hormone loss increased both the Aβ level and neuritic plaque deposition in 2×TgAD mice. Therefore, autophagy may play an important role in the pathogenesis of female AD, which is also expected to help post-menopausal patients with AD.

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“…In these diseases, neurons are more frequently affected because they are probably more sensitive to mutant proteins than other cell types and, since they do not divide, mutant polyQ proteins more quickly accumulate in these cells. Clearance of misfolded and mutant proteins is mostly accomplished by the Ubiquitin Proteasome System (UPS) and even more so by autophagy, processes of high relevance in neurons and whose activities appear to decrease during the course of the disease . Nevertheless, mutant proteins are generally ubiquitously expressed throughout the body and affected peripheral cells might also contribute to the disease process .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Duarte‐Silva

Maciel

2016

Medicinal Research Reviews

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Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.

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Brain metabolism as a modulator of autophagy in neurodegeneration

Cited by 19 publications

References 149 publications

Stress and the nonsense-mediated RNA decay pathway

Stress and the nonsense-mediated RNA decay pathway

Effects of ovarian hormone loss on neuritic plaques and autophagic flux in the brains of adult female APP/PS1 double-transgenic mice

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

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