bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023‒04‒16
ten papers selected by
Rich Giadone
Harvard University
  1. Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons.
  2. Ageing studies in five animals suggest how to reverse decline.
  3. TUG-891 inhibits neuronal endoplasmic reticulum stress and pyroptosis activation and protects neurons in a mouse model of intraventricular hemorrhage.
  4. Disagreement among the three musketeers of the unfolded protein response.
  5. Metabolic regulation of misfolded protein import into mitochondria.
  6. Ageing-associated changes in transcriptional elongation influence longevity.
  7. The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration.
  8. Daily briefing: A cellular cause of ageing (and how to reverse it).
  9. Activation of AMPK promotes cardiac differentiation by stimulating the autophagy pathway.
  10. Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation.
  1. bioRxiv. 2023 Mar 27. pii: 2023.03.27.534444. [Epub ahead of print]
    Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons.
    Ching-Chieh Chou, Ryan Vest, Miguel A Prado, Joshua Wilson-Grady, Joao A Paulo, Yohei Shibuya, Patricia Moran-Losada, Ting-Ting Lee, Jian Luo, Steven P Gygi, Jeffery W Kelly, Daniel Finley, Marius Wernig, Tony Wyss-Coray, Judith Frydman.
      The role of proteostasis and organelle homeostasis dysfunction in human aging and Alzheimer's disease (AD) remains unclear. Analyzing proteome-wide changes in human donor fibroblasts and their corresponding transdifferentiated neurons (tNeurons), we find aging and AD synergistically impair multiple proteostasis pathways, most notably lysosomal quality control (LQC). In particular, we show that ESCRT-mediated lysosomal repair defects are associated with both sporadic and PSEN1 familial AD. Aging- and AD-linked defects are detected in fibroblasts but highly exacerbated in tNeurons, leading to enhanced neuronal vulnerability, unrepaired lysosomal damage, inflammatory factor secretion and cytotoxicity. Surprisingly, tNeurons from aged and AD donors spontaneously develop amyloid-β inclusions co-localizing with LQC markers, LAMP1/2-positive lysosomes and proteostasis factors; we observe similar inclusions in brain tissue from AD patients and APP-transgenic mice. Importantly, compounds enhancing lysosomal function broadly ameliorate these AD-associated pathologies. Our findings establish cell-autonomous LQC dysfunction in neurons as a central vulnerability in aging and AD pathogenesis.
    DOI:  https://doi.org/10.1101/2023.03.27.534444
  2. Nature. 2023 Apr 12.
    Ageing studies in five animals suggest how to reverse decline.
    Gemma Conroy.
      
    Keywords:  Ageing; Molecular biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-023-01040-x
  3. Neural Regen Res. 2023 Oct;18(10): 2278-2284
    TUG-891 inhibits neuronal endoplasmic reticulum stress and pyroptosis activation and protects neurons in a mouse model of intraventricular hemorrhage.
    Hao-Xiang Wang, Chang Liu, Yuan-You Li, Yi Cao, Long Zhao, Yan-Jie Zhao, Zi-Ang Deng, Ai-Ping Tong, Liang-Xue Zhou.
      Pyroptosis plays an important role in hemorrhagic stroke. Excessive endoplasmic reticulum stress can cause endoplasmic reticulum dysfunction and cellular pyroptosis by regulating the nucleotide-binding oligomerization domain and leucine-rich repeat pyrin domain-containing protein 3 (NLRP3) pathway. However, the relationship between pyroptosis and endoplasmic reticulum stress after intraventricular hemorrhage is unclear. In this study, we established a mouse model of intraventricular hemorrhage and found pyroptosis and endoplasmic reticulum stress in brain tissue. Intraperitoneal injection of the selective GPR120 agonist TUG-891 inhibited endoplasmic reticulum stress, pyroptosis, and inflammation and protected neurons. The neuroprotective effect of TUG-891 appears related to inhibition of endoplasmic reticulum stress and pyroptosis activation.
    Keywords:  GPR120; GSDMD; NLRP3; TUG-891; ameliorating inflammation; endoplasmic reticulum stress; hemorrhagic stroke; neurological function; pyroptosis; unfolded protein response
    DOI:  https://doi.org/10.4103/1673-5374.369116
  4. J Cell Biol. 2023 May 01. pii: e202304013. [Epub ahead of print]222(5):
    Disagreement among the three musketeers of the unfolded protein response.
    András Jipa, Gábor Juhász.
      Jipa and Juhász preview results from the lab of Tao Wang (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202208147) which show a surprising antagonism between two branches of the unfolded protein response that dictates disease progression in a model of autosomal dominant retinitis pigmentosa.
    DOI:  https://doi.org/10.1083/jcb.202304013
  5. bioRxiv. 2023 Mar 29. pii: 2023.03.29.534670. [Epub ahead of print]
    Metabolic regulation of misfolded protein import into mitochondria.
    Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.
      Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins are imported into and degraded inside mitochondria. In this study, a genome-wide screen in yeast uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of misfolded proteins into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by misfolded proteins such as those associated with neurodegenerative diseases.
    DOI:  https://doi.org/10.1101/2023.03.29.534670
  6. Nature. 2023 Apr 12.
    Ageing-associated changes in transcriptional elongation influence longevity.
    Cédric Debès, Antonios Papadakis, Sebastian Grönke, Özlem Karalay, Luke S Tain, Athanasia Mizi, Shuhei Nakamura, Oliver Hahn, Carina Weigelt, Natasa Josipovic, Anne Zirkel, Isabell Brusius, Konstantinos Sofiadis, Mantha Lamprousi, Yu-Xuan Lu, Wenming Huang, Reza Esmaillie, Torsten Kubacki, Martin R Späth, Bernhard Schermer, Thomas Benzing, Roman-Ulrich Müller, Adam Antebi, Linda Partridge, Argyris Papantonis, Andreas Beyer.
      Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.
    DOI:  https://doi.org/10.1038/s41586-023-05922-y
  7. Int J Mol Sci. 2023 Apr 02. pii: 6639. [Epub ahead of print]24(7):
    The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration.
    Mirco Masi, Fabrizio Biundo, André Fiou, Marco Racchi, Alessia Pascale, Erica Buoso.
      Amyloid Precursor Protein (APP) and its cleavage processes have been widely investigated in the past, in particular in the context of Alzheimer's Disease (AD). Evidence of an increased expression of APP and its amyloidogenic-related cleavage enzymes, β-secretase 1 (BACE1) and γ-secretase, at the hit axon terminals following Traumatic Brain Injury (TBI), firstly suggested a correlation between TBI and AD. Indeed, mild and severe TBI have been recognised as influential risk factors for different neurodegenerative diseases, including AD. In the present work, we describe the state of the art of APP proteolytic processing, underlining the different roles of its cleavage fragments in both physiological and pathological contexts. Considering the neuroprotective role of the soluble APP alpha (sAPPα) fragment, we hypothesised that sAPPα could modulate the expression of genes of interest for AD and TBI. Hence, we present preliminary experiments addressing sAPPα-mediated regulation of BACE1, Isthmin 2 (ISM2), Tetraspanin-3 (TSPAN3) and the Vascular Endothelial Growth Factor (VEGFA), each discussed from a biological and pharmacological point of view in AD and TBI. We finally propose a neuroprotective interaction network, in which the Receptor for Activated C Kinase 1 (RACK1) and the signalling cascade of PKCβII/nELAV/VEGF play hub roles, suggesting that vasculogenic-targeting therapies could be a feasible approach for vascular-related brain injuries typical of AD and TBI.
    Keywords:  BACE1; ELAV; ISM2; PKC; RACK1; TSPAN3; VEGF; secretase
    DOI:  https://doi.org/10.3390/ijms24076639
  8. Nature. 2023 Apr 13.
    Daily briefing: A cellular cause of ageing (and how to reverse it).
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-023-01290-9
  9. J Cell Commun Signal. 2023 Apr 11.
    Activation of AMPK promotes cardiac differentiation by stimulating the autophagy pathway.
    Mina Kolahdouzmohammadi, Sara Pahlavan, Fattah Sotoodehnejadnematalahi, Yaser Tahamtani, Mehdi Totonchi.
      Autophagy, a critical catabolic process for cell survival against different types of stress, has a role in the differentiation of various cells, such as cardiomyocytes. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is an energy-sensing protein kinase involved in the regulation of autophagy. In addition to its direct role in regulating autophagy, AMPK can also influence other cellular processes by regulating mitochondrial function, posttranslational acetylation, cardiomyocyte metabolism, mitochondrial autophagy, endoplasmic reticulum stress, and apoptosis. As AMPK is involved in the control of various cellular processes, it can influence the health and survival of cardiomyocytes. This study investigated the effects of an AMPK inducer (Metformin) and an autophagy inhibitor (Hydroxychloroquine) on the differentiation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). The results showed that autophagy was upregulated during cardiac differentiation. Furthermore, AMPK activation increased the expression of CM-specific markers in hPSC-CMs. Additionally, autophagy inhibition impaired cardiomyocyte differentiation by targeting autophagosome-lysosome fusion. These results indicate the significance of autophagy in cardiomyocyte differentiation. In conclusion, AMPK might be a promising target for the regulation of cardiomyocyte generation by in vitro differentiation of pluripotent stem cells.
    Keywords:  AMPK; Autophagy; Cardiomyocyte differentiation; Hydroxychloroquine; Metformin
    DOI:  https://doi.org/10.1007/s12079-023-00744-z
  10. Curr Med Chem. 2023 Apr 09.
    Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation.
    Haiyang Zhong, Hongli Liu, Huanxiang Liu.
      Tau dysfunction has a close association with many neurodegenerative diseases, which are collectively referred to as tauopathies. Neurofibrillary tangles (NFTs) formed by misfolding and aggregation of tau are the main pathological process of tauopathy. Therefore, uncovering the misfolding and aggregation mechanism of tau protein will help to reveal the pathogenic mechanism of tauopathies. Molecular dynamics (MD) simulation is well suited for studying the dynamic process of protein structure changes. It provides detailed information on protein structure changes over time at the atomic resolution. At the same time, MD simulation can also simulate various conditions conveniently. Based on these advantages, MD simulations are widely used to study conformational transition problems such as protein misfolding and aggregation. Here, we summarized the structural features of tau, the factors affecting its misfolding and aggregation, and the applications of MD simulations in the study of tau misfolding and aggregation.
    Keywords:  Tau protein; aggregation; misfolding; molecular dynamics simulation; mutation; post-translational modifications
    DOI:  https://doi.org/10.2174/0929867330666230409145247
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