bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023‒04‒02
ten papers selected by
Rich Giadone
Harvard University
  1. Profiling the Hsp70 Chaperone Network in Heat-Induced Proteotoxic Stress Models of Human Neurons.
  2. Editorial: Restoring endoplasmic reticulum proteostasis to treat neurological disorders.
  3. Association of Hsp90 with p53 and Fizzy related homolog (Fzr) synchronizing Anaphase Promoting Complex (APC/C): An unexplored ally towards oncogenic pathway.
  4. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress.
  5. Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy.
  6. ERnet: a tool for the semantic segmentation and quantitative analysis of endoplasmic reticulum topology.
  7. Autophagy at the synapse, an early site of dysfunction in neurodegeneration.
  8. Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice.
  9. Jintiange proteins promote osteogenesis and inhibit apoptosis of osteoblasts by enhancing autophagy via PI3K/AKT and ER stress pathways.
  10. The Effect of Ketamine on Endoplasmic Reticulum Stress in Rats with Neuropathic Pain.
  1. Biology (Basel). 2023 Mar 09. pii: 416. [Epub ahead of print]12(3):
    Profiling the Hsp70 Chaperone Network in Heat-Induced Proteotoxic Stress Models of Human Neurons.
    Bothina Mohammed Alharbi, Tahani H Albinhassan, Razan Ali Alzahrani, Abderrezak Bouchama, Sameer Mohammad, Awatif Abdulaziz Alomari, May Nasser Bin-Jumah, Entissar S AlSuhaibani, Shuja Shafi Malik.
      Heat stroke is among the most hazardous hyperthermia-related illnesses and an emerging threat to humans from climate change. Acute brain injury and long-lasting brain damage are the hallmarks of this condition. Hyperthermic neurological manifestations are remarkable for their damage correlation with stress amplitude and long-term persistence. Hyperthermia-induced protein unfolding, and nonspecific aggregation accumulation have neurotoxic effects and contribute to the pathogenesis of brain damage in heat stroke. Therefore, we generated heat-induced, dose-responsive extreme and mild proteotoxic stress models in medulloblastoma [Daoy] and neuroblastoma [SH-SY5Y] and differentiated SH-SY5Y neuronal cells. We show that heat-induced protein aggregation is associated with reduced cell proliferation and viability. Higher protein aggregation in differentiated neurons than in neuroblastoma precursors suggests a differential neuronal vulnerability to heat. We characterized the neuronal heat shock response through RT-PCR array analysis of eighty-four genes involved in protein folding and protein quality control (PQC). We identify seventeen significantly expressed genes, five of which are Hsp70 chaperones, and four of their known complementing function proteins. Protein expression analysis determined the individual differential contribution of the five Hsp70 chaperones to the proteotoxic stress response and the significance of only two members under mild conditions. The co-expression analysis reveals significantly high co-expression between the Hsp70 chaperones and their interacting partners. The findings of this study lend support to the hypothesis that hyperthermia-induced proteotoxicity may underlie the brain injury of heat stroke. Additionally, this study presents a comprehensive map of the Hsp70 network in these models with potential clinical and translational implications.
    Keywords:  Hsp70 proteins; chaperones; heat shock; neurons; proteostasis; stress response
    DOI:  https://doi.org/10.3390/biology12030416
  2. Front Pharmacol. 2023 ;14 1176805
    Editorial: Restoring endoplasmic reticulum proteostasis to treat neurological disorders.
    Danilo B Medinas, Najla Arshad, Sonam Parakh, Sayuri Miyamoto, Vanessa Olzon Zambelli.
      
    Keywords:  drug discovery; endoplasmic reticulum; ischemia-reperfusion injury; neurological disorders; proteostasis; small molecules; spinal cord injury; unfolded protein response
    DOI:  https://doi.org/10.3389/fphar.2023.1176805
  3. Biochim Biophys Acta Rev Cancer. 2023 Mar 25. pii: S0304-419X(23)00032-X. [Epub ahead of print] 188883
    Association of Hsp90 with p53 and Fizzy related homolog (Fzr) synchronizing Anaphase Promoting Complex (APC/C): An unexplored ally towards oncogenic pathway.
    Sanghati Roy Chowdhury, Tirthankar Koley, Mandeep Singh, Ethayathulla Abdul Samath, Punit Kaur.
      The intricate molecular interactions leading to the oncogenic pathway are the consequence of cell cycle modification controlled by a bunch of cell cycle regulatory proteins. The tumor suppressor and cell cycle regulatory proteins work in coordination to maintain a healthy cellular environment. The integrity of this cellular protein pool is perpetuated by heat shock proteins/chaperones, which assist in proper protein folding during normal and cellular stress conditions. Among these versatile groups of chaperone proteins, Hsp90 is one of the significant ATP-dependent chaperones that aid in stabilizing many tumor suppressors and cell cycle regulator protein targets. Recently, studies have revealed that in cancerous cell lines, Hsp90 stabilizes mutant p53, 'the guardian of the genome.' Hsp90 also has a significant impact on Fzr, an essential regulator of the cell cycle having an important role in the developmental process of various organisms, including Drosophila, yeast, Caenorhabditis elegans, and plants. During cell cycle progression, p53 and Fzr coordinately regulate the Anaphase Promoting Complex (APC/C) from metaphase to anaphase transition up to cell cycle exit. APC/C mediates proper centrosome function in the dividing cell. The centrosome acts as the microtubule organizing center for the correct segregation of the sister chromatids to ensure perfect cell division. This review examines the structure of Hsp90 and its co-chaperones, which work in synergy to stabilize proteins such as p53 and Fizzy-related homolog (Fzr) to synchronize the Anaphase Promoting Complex (APC/C). Dysfunction of this process activates the oncogenic pathway leading to the development of cancer. Additionally, an overview of current drugs targeting Hsp90 at various phases of clinical trials has been included.
    Keywords:  Anaphase Promoting Complex (APC/C); Cell cycle; Fizzy related homolog (Fzr); Hsp90; Oncogenesis; p53
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188883
  4. bioRxiv. 2023 Mar 27. pii: 2023.03.19.533325. [Epub ahead of print]
    A beneficial adaptive role for CHOP in driving cell fate selection during ER stress.
    Kaihua Liu, Chaoxian Zhao, D Thomas Rutkowski.
      Cellular stresses elicit signaling cascades that are capable of both mitigating the inciting dysfunction and initiating cell death when the stress cannot be overcome. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. Yet CHOP carries out this function largely by augmenting protein synthesis, which is an essential component of recovery from stress. In addition, the mechanisms that drive cell fate during ER stress have largely been explored under super-physiological experimental conditions that do not permit cellular adaptation. Thus, it is not clear whether CHOP also has a beneficial role during that adaptation. Here, we have created a new, versatile, genetically modified Chop allele, which we combined with single cell analysis and stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Surprisingly, we found that, within the cell population, CHOP paradoxically promoted death in some cells but proliferation-and hence recovery-in others. Strikingly, this function of CHOP conferred a stress-specific competitive growth advantage to wild-type cells over cells lacking CHOP. The dynamics of CHOP expression and UPR activation at the single cell level suggested that, by promoting protein synthesis, CHOP maximizes UPR activation which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates-adaptation or death-during stress. They point to a previously unappreciated pro-survival function of CHOP during stresses of physiological intensity.
    DOI:  https://doi.org/10.1101/2023.03.19.533325
  5. bioRxiv. 2023 Mar 18. pii: 2023.03.17.533015. [Epub ahead of print]
    Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy.
    Xianzun Tao, Jiaqi Liu, Zoraida Diaz-Perez, Jackson R Foley, Tracy Murray Stewart, Robert A Casero, R Grace Zhai.
      Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. In the present study we investigated the role of spermine synthase (SMS) in autophagy regulation and tau protein processing in Drosophila and human cellular models of Tauopathy. Our previous study showed that Drosophila spermine synthase ( dSms ) deficiency impairs lysosomal function and blocks autophagy flux. Interestingly, partial loss-of-function of SMS in heterozygous dSms flies extends lifespan and improves the climbing performance of flies with human Tau (hTau) overexpression. Mechanistic analysis showed that heterozygous loss-of-function mutation of dSms reduces hTau protein accumulation through enhancing autophagic flux. Measurement of polyamine levels detected a mild elevation of spermidine in flies with heterozygous loss of dSms . SMS knock-down in human neuronal or glial cells also upregulates autophagic flux and reduces Tau protein accumulation. Proteomics analysis of postmortem brain tissue from AD patients showed a significant albeit modest elevation of SMS protein level in AD-relevant brain regions compared to that of control brains consistently across several datasets. Taken together, our study uncovers a correlation between SMS protein level and AD pathogenesis and reveals that SMS reduction upregulates autophagy, promotes Tau clearance, and reduces Tau protein accumulation. These findings provide a new potential therapeutic target of Tauopathy.
    DOI:  https://doi.org/10.1101/2023.03.17.533015
  6. Nat Methods. 2023 Mar 30.
    ERnet: a tool for the semantic segmentation and quantitative analysis of endoplasmic reticulum topology.
    Meng Lu, Charles N Christensen, Jana M Weber, Tasuku Konno, Nino F Läubli, Katharina M Scherer, Edward Avezov, Pietro Lio, Alexei A Lapkin, Gabriele S Kaminski Schierle, Clemens F Kaminski.
      The ability to quantify structural changes of the endoplasmic reticulum (ER) is crucial for understanding the structure and function of this organelle. However, the rapid movement and complex topology of ER networks make this challenging. Here, we construct a state-of-the-art semantic segmentation method that we call ERnet for the automatic classification of sheet and tubular ER domains inside individual cells. Data are skeletonized and represented by connectivity graphs, enabling precise and efficient quantification of network connectivity. ERnet generates metrics on topology and integrity of ER structures and quantifies structural change in response to genetic or metabolic manipulation. We validate ERnet using data obtained by various ER-imaging methods from different cell types as well as ground truth images of synthetic ER structures. ERnet can be deployed in an automatic high-throughput and unbiased fashion and identifies subtle changes in ER phenotypes that may inform on disease progression and response to therapy.
    DOI:  https://doi.org/10.1038/s41592-023-01815-0
  7. Curr Opin Physiol. 2023 Apr;pii: 100631. [Epub ahead of print]32
    Autophagy at the synapse, an early site of dysfunction in neurodegeneration.
    Hilary Grosso Jasutkar, Ai Yamamoto.
      Macroautophagy, herein referred to as autophagy, has long been implicated in the pathophysiology of neurodegenerative diseases. However, an incomplete understanding of how autophagy contributes to disease pathogenesis has limited progress in acting on this potential target for the development of disease modifying therapeutics. Research in the past few decades has revealed that autophagy plays a specialized role in the synapse, a site of early dysfunction in multiple neurodegenerative diseases. In this review we discuss the evidence suggesting that inadequate autophagy at the synapse may contribute to neurodegeneration, and why the functions of autophagy may be particularly relevant for synaptic function.
    Keywords:  autophagy; neurodegeneration; selective autophagy; synapse
    DOI:  https://doi.org/10.1016/j.cophys.2023.100631
  8. Aging Cell. 2023 Mar 25. e13825
    Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice.
    Junyeop Kim, Yerim Hwang, Sumin Kim, Yujung Chang, Yunkyung Kim, Youngeun Kwon, Jongpil Kim.
      Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). We observed that the dCas9-Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization. Moreover, the progerin accumulation in HGPS aorta was significantly suppressed by the dCas9 activator-mediated Oct4 induction. Importantly, CRISPR/dCas9-activated Oct4 expression rescued the HGPS-associated vascular pathological features and lifespan shortening in the mouse model. These results suggest that partial rejuvenation via CRISPR/dCas9-mediated Oct4 activation can be used as a novel strategy in treating geriatric diseases.
    Keywords:  CRISPR/dCas9; Hutchinson-Gilford progeria syndrome; Oct4; aging; rejuvenation
    DOI:  https://doi.org/10.1111/acel.13825
  9. J Ethnopharmacol. 2023 Mar 28. pii: S0378-8741(23)00267-2. [Epub ahead of print] 116399
    Jintiange proteins promote osteogenesis and inhibit apoptosis of osteoblasts by enhancing autophagy via PI3K/AKT and ER stress pathways.
    Yuling Liu, Luying Zhao, Xinyunxi He, Yi Shen, Na Wang, Sijing Hu, Jinlong Xu, Qiming Zhao, Quanlong Zhang, Luping Qin, Qiaoyan Zhang.
      ETHNOPHARMACOLOGICAL RELEVANCE: Tiger bone, which had long been used in traditional Chinese medicine, had the action of removing wind and alleviating pain, strengthening the sinews and bones, and often used to treat bone impediment, and atrophic debility of bones in TCM clinical practice. As a substitute of natural bone tiger, artificial tiger bone Jintiange (JTG), has been approved by the State Food and Drug Administration of China for relief the symptom of osteoporosis, such as lumbago and back pain, lassitude in loin and legs, flaccidity and weakness legs, and walk with difficulty based on TCM theory. JTG has similar chemical profile to natural tiger bone, and contains mineral substance, peptides and proteins, and has been shown to protect bone loss in ovariectomized mice and exert the regulatory effects on osteoblast and osteoclast activities. But how the peptides and proteins in JTG modulate bone formation remains unclear.AIM: To investigate the stimulating effects of JTG proteins on osteogenesis and explore the possible underlying mechanisms.
    MATERIALS AND METHODS: JTG proteins were prepared from JTG Capsules by extracting calcium, phosphorus and other inorganic elements using SEP-PaktC18 desalting column. MC3T3-E1 cells were treated with JTG proteins to evaluate their effects and explore the underlying mechanisms. Osteoblast proliferation was detected by CCK-8 method. ALP activity was detected using a relevant assay kit, and bone mineralized nodules were stained with alizarin red-Tris-HCl solution. Cell apoptosis was analyzed by flow cytometry. Autophagy was observed by MDC staining, and autophagosomes were observed by TEM. Nuclear translocations of LC3 and CHOP were detected by immunofluorescence and observed under a laser confocal microscope. The expression of key proteins related to osteogenesis, apoptosis, autophagy and PI3K/AKT and ER stress pathways was analyzed by Western Blot analysis.
    RESULTS: JTG proteins improved osteogenesis as evidenced by the alteration of proliferation, differentiation and mineralization of MC3T3-E1 osteoblasts, inhibited their apoptosis, and enhanced autophagosome formation and autophagy. They also regulated the expression of key proteins of PI3K/AKT and ER stress pathways. In addition, PI3K/AKT and ER stress pathway inhibitors could reverse the regulatory effects of JTG proteins on osteogenesis, apoptosis, autophagy and PI3K/AKT and ER stress pathways.
    CONCLUSION: JTG proteins increased the osteogenesis and inhibited osteoblast apoptosis by enhancing autophagy via PI3K/AKT and ER stress signaling pathways.
    Keywords:  Autophagy; Endoplasmic reticulum (ER) stress; Jintiange capsule; Osteogenesis; PI3K/AKT pathway
    DOI:  https://doi.org/10.1016/j.jep.2023.116399
  10. Int J Mol Sci. 2023 Mar 10. pii: 5336. [Epub ahead of print]24(6):
    The Effect of Ketamine on Endoplasmic Reticulum Stress in Rats with Neuropathic Pain.
    Eun-Hye Seo, Liyun Piao, Eun-Hwa Cho, Seung-Wan Hong, Seong-Hyop Kim.
      This study aimed to investigate the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on endoplasmic reticulum (ER) stress in rats with neuropathic pain (NP). NP was induced in rats through ligation and transection of the sciatic nerve. After confirmation of NP, the animals were randomly divided into ketamine and control groups. The ketamine group was administered 50 mg/kg of ketamine at 15, 18, and 21 days after surgery. The expression of NMDA receptor subtype 2B (NR2B) and ER stress markers in the spinal cord (L5) was evaluated. The ipsilateral side of the surgery in the ketamine group was less sensitive to mechanical and cold stimulations. The expression of NR2B on the ipsilateral side was significantly lower in the ketamine group than in the control group (18.93 ± 1.40% vs. 31.08 ± 0.74%, p < 0.05). All markers for ER stress on the ipsilateral side of the surgery in both groups had higher expression than those on the contralateral side. The expression of activating transcription factor-6 (ATF-6) on the ipsilateral side was significantly lower in the ketamine group than in the control group (p < 0.05). Systemic administration of ketamine inhibited the expression of NMDA receptors and improved NP symptoms. Among the markers of ER stress, the therapeutic effect of ketamine is associated with the inhibition of ATF-6 expression.
    Keywords:  ER stress; N-methyl-D-aspartate receptor subtype 2B; activating transcription factor-6; ketamine; neuropathic pain
    DOI:  https://doi.org/10.3390/ijms24065336
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