PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy

Zhang, Hanming; Pan, Bo; Wu, Penglong; Parajuli, Nirmal; Rekhter, Mark D.; Goldberg, Alfred L.; Wang, Xuejun

doi:10.1126/sciadv.aaw5870

Cited by 52 publications

(64 citation statements)

References 40 publications

(126 reference statements)

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“…A key difference between proteasomal and lysosomal-mediated degradation is that short-lived proteins (like the tumor suppressor p53) are degraded by the proteasome, whereas long-lived proteins (like myosin and actin) and large protein complexes (like chaperonin containing TCP-1 complex) [43] which cannot traffic to the narrow proteasomal core, undergo lysosomal degradation [44]. Misfolded proteins including the mutant form of crystallin protein and alpha-synuclein mutant protein are degraded by both systems [45][46][47].…”

Section: Ubiquitin Proteasome Systemmentioning

confidence: 99%

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Ghosh

Vinod

Symons

et al. 2020

Cells

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Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.

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Section: Ubiquitin Proteasome Systemmentioning

confidence: 99%

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Ghosh

Vinod

Symons

et al. 2020

Cells

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“…The proteins were visualized using appropriate horseradish peroxidase-conjugated secondary antibodies and an enhanced chemiluminescence reagent. The signals of specific proteins were detected using a Gel Doc imager (Bio-Rad) and were expressed as a fraction of the signal of the control protein [48,49].…”

Section: Western Blot Analysismentioning

confidence: 99%

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

Zhao

et al. 2020

J Neuroinflammation

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Background: Alzheimer's disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods: The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis. Results: Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions: Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the antiinflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

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“…Ubiquitin tagging of aggregateprone proteins is essential for their efficient removal (Galves et al, 2019). However, studies have documented impairment in the ubiquitin proteasome pathways by mutant αB-crystallin (R120G) (Chen et al, 2005;Zhang et al, 2010Zhang et al, , 2019Gupta et al, 2014) and desmin mutants (Liu et al, 2006a,b) that are linked to cardiomyopathy in humans; suggesting that worsening protein aggregate pathology is linked at least in part to progressive impairment in this arm of the protein quality control machinery. Moreover, recent studies conclusively demonstrate rapid development of fulminant cardiomyopathy and death in mice lacking Psmc1 (that encodes for an essential component of the 19S proteasome subunit) (Pan et al, 2020); with concomitant upregulation of the autophagy-lysosome machinery as an adaptive response to remove accumulated protein aggregates.…”

Section: Proteostatic Failure In Heart Disease: the Devil In The Heartmentioning

confidence: 99%

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

2020

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Homeostasis in vertebrate systems is contingent on normal cardiac function. This, in turn, depends on intricate protein-based cellular machinery, both for contractile function, as well as, durability of cardiac myocytes. The cardiac small heat shock protein (csHsp) chaperone system, highlighted by αB-crystallin (CRYAB), a small heat shock protein (sHsp) that forms ∼3-5% of total cardiac mass, plays critical roles in maintaining proteostatic function via formation of self-assembled multimeric chaperones. In this work, we review these ancient proteins, from the evolutionarily preserved role of homologs in protists, fungi and invertebrate systems, as well as, the role of sHsps and chaperones in maintaining cardiac myocyte structure and function. We propose the concept of the "sarcostat" as a protein quality control mechanism in the sarcomere. The roles of the proteasomal and lysosomal proteostatic network, as well as, the roles of the aggresome, self-assembling protein complexes and protein aggregation are discussed in the context of cardiac myocyte homeostasis. Finally, we will review the potential for targeting the csHsp system as a novel therapeutic approach to prevent and treat cardiomyopathy and heart failure.

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PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy

Cited by 52 publications

References 40 publications

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

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