Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Abstract: Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.

Dietary Vitamin B12 reduces amyloid-β proteotoxicity by alleviating oxidative stress and mitochondrial dysfunction

Abstract: Alzheimers disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis including amyloid beta (A{beta}) deposition, mitochondrial dysfunction, and oxidative stress. Here we used Caenorhabditis elegans to define the impact of diet on A{beta} proteotoxicity. We discovered that dietary vitamin B12 alleviated mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying A{beta}-induced paralysis without affecting A{beta} accumulation. Vitamin B12 had this protective effect by acting as a cofactor for methionine synthase rather than as an antioxidant. Vitamin supplementation of B12 deficient adult A{beta} animals was beneficial, demonstrating potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by both aging and proteotoxic stress.

Graptopetalum paraguayense Extract Ameliorates Proteotoxicity in Aging and Age-Related Diseases in Model Systems

Abstract: Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer’s disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses β-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.

Deciphering the Proteotoxic Stress Responses Triggered by the Perturbed Thylakoid Proteostasis in Arabidopsis

Abstract: Here, we explored heat dependent thylakoid FtsH protease substrates and investigated proteotoxicity induced by thermal damage and processive protease dysfunction on the thylakoid membrane. Through our thylakoid enriched proteome analysis and biochemical experiments, carbonylated stromal proteins were suggested as possible FtsH targets. Furthermore, we observed in the thylakoid fractions in the absence of FtsH stromal reactive oxygen species-detoxifying enzymes, as well as heat shock proteins and chaperones, which are known to be upregulated at the transcriptional level when this protease is absent, which is called the damaged protein response, resembling unfolded protein response in eukaryotic cells. Interestingly, the thylakoid-enriched high-density fractions included stromal translation factors and RNA-binding proteins, along with aminoacyl-tRNA synthetase, reminiscent of the formation of stress granules. Unexpectedly, extraplastid proteins such as mitochondrial chaperones, peroxidase, tricarboxylic acid cycle and respiratory chain enzymes, as well as cytosolic ribosomes, translation factors, heat shock proteins, antioxidants and metabolic enzymes, were also found deposited in the high-density fractions depending on the loss of thylakoid FtsH, with more prominent effects of thermal stress on the cytosolic proteins. This may reflect intracellular adaptation to the proteotoxic influences from the organelle.

The E2 ubiquitin-conjugating enzyme HIP2 is a crucial regulator of quality control against mutant SOD1 proteotoxicity

Abstract: Mutations in superoxide dismutase 1 (SOD1) leading to the formation of intracellular protein aggregates cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of motor neurons. The ALS-linked mutant SOD1 emerged as a possible target for ubiquitin-proteasome system (UPS)-mediated degradation. We aimed to elucidate the role of huntingtin interaction protein 2 (HIP2), an E2 ubiquitin-conjugating enzyme, in the proteotoxicity of mutant SOD1 aggregates. We found that HIP2 interacts with mutant SOD1, but not wild-type SOD1, and is upregulated in response to mutant SOD1 expression. Upregulation of HIP2 protein was observed in the spinal cord of 16-week-old SOD1-G93A transgenic mice. HIP2 further modified mutant SOD1 proteins via K48-linked polyubiquitination and degraded mutant SOD1 proteins through the UPS. Upregulation of HIP2 protected cells from mutant SOD1-induced toxicity. Taken together, our findings demonstrate that HIP2 is a crucial regulator of quality control against the proteotoxicity of mutant SOD1. Our results suggest that modulating HIP2 may represent a novel therapeutic strategy for the treatment of ALS.