bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–06–11
fourteen papers selected by
Rich Giadone, Harvard University
  1. Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer's Disease mice.
  2. Profiling of purified autophagic vesicle degradome in the maturing and aging brain.
  3. The Roles of Molecular Chaperones in Regulating Cell Metabolism.
  4. Beyond Protein Folding: Exploring the Role of Unfolded Protein Response in Axon Targeting.
  5. A cytosolic surveillance mechanism activates the mitochondrial UPR.
  6. Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.
  7. Cellular and animal models to investigate pathogenesis of amyloid aggregation in neurodegenerative diseases.
  8. Taurine linked with healthy aging.
  9. mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes.
  10. Hypoxia prevents premature ageing in mice.
  11. Single-cell transcriptomics identifies perturbed molecular pathways in midbrain organoids using α-Synuclein triplication Parkinson's Disease patient-derived iPSCs.
  12. BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology.
  13. Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases.
  14. Toward a standard model for autophagosome biogenesis.
  1. bioRxiv. 2023 May 24. pii: 2023.05.23.541973. [Epub ahead of print]
    Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer's Disease mice.
    Jennifer M Hafycz, Ewa Strus, Nirinjini N Naidoo.
      Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is pervasive among the aging population. Two distinct phenotypes of AD are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock-in mouse model of AD and several protein chaperone supplementation paradigms, including a late-stage intervention. We show that supplementing protein chaperones systemically and locally in the hippocampus reduces PERK signaling and increases XBP1s, which is associated with increased ADAM10 and decreased Aβ42. Importantly, chaperone treatment improves cognition which is correlated with increased CREB phosphorylation and BDNF. Together, this data suggests that chaperone treatment restores proteostasis in a mouse model of AD and that this restoration is associated with improved cognition and reduced pathology.
    One-sentence summary: Chaperone therapy in a mouse model of Alzheimer's disease improves cognition by reducing chronic UPR activity.
    DOI:  https://doi.org/10.1101/2023.05.23.541973
  2. Neuron. 2023 May 26. pii: S0896-6273(23)00384-7. [Epub ahead of print]
    Profiling of purified autophagic vesicle degradome in the maturing and aging brain.
    Emmanouela Kallergi, Devanarayanan Siva Sankar, Alessandro Matera, Angeliki Kolaxi, Rosa Chiara Paolicelli, Joern Dengjel, Vassiliki Nikoletopoulou.
      Autophagy disorders prominently affect the brain, entailing neurodevelopmental and neurodegenerative phenotypes in adolescence or aging, respectively. Synaptic and behavioral deficits are largely recapitulated in mouse models with ablation of autophagy genes in brain cells. Yet, the nature and temporal dynamics of brain autophagic substrates remain insufficiently characterized. Here, we immunopurified LC3-positive autophagic vesicles (LC3-pAVs) from the mouse brain and proteomically profiled their content. Moreover, we characterized the LC3-pAV content that accumulates after macroautophagy impairment, validating a brain autophagic degradome. We reveal selective pathways for aggrephagy, mitophagy, and ER-phagy via selective autophagy receptors, and the turnover of numerous synaptic substrates, under basal conditions. To gain insight into the temporal dynamics of autophagic protein turnover, we quantitatively compared adolescent, adult, and aged brains, revealing critical periods of enhanced mitophagy or degradation of synaptic substrates. Overall, this resource unbiasedly characterizes the contribution of autophagy to proteostasis in the maturing, adult, and aged brain.
    Keywords:  ER-phagy; aggrephagy; autophagic vesicles; brain; degradome; mitophagy; proteomic profiling; synapse
    DOI:  https://doi.org/10.1016/j.neuron.2023.05.011
  3. FEBS Lett. 2023 Jun 07.
    The Roles of Molecular Chaperones in Regulating Cell Metabolism.
    Matthew J Binder, Anthony M Pedley.
      Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post-translational modifications and metabolite-based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.
    Keywords:  cellular metabolism; metabolons; molecular chaperones; protein degradation; protein folding; supramolecular complexes
    DOI:  https://doi.org/10.1002/1873-3468.14682
  4. Mol Cells. 2023 06 30. 46(6): 348-350
    Beyond Protein Folding: Exploring the Role of Unfolded Protein Response in Axon Targeting.
    Soo Jeong Kim.
      
    DOI:  https://doi.org/10.14348/molcells.2023.0061
  5. Nature. 2023 Jun 07.
    A cytosolic surveillance mechanism activates the mitochondrial UPR.
    F X Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch.
      The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
    DOI:  https://doi.org/10.1038/s41586-023-06142-0
  6. Front Neurosci. 2023 ;17 1082047
    Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.
    Stefania Santarelli, Chiara Londero, Alessia Soldano, Carlotta Candelaresi, Leonardo Todeschini, Luisa Vernizzi, Paola Bellosta.
      Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.
    Keywords:  Drosophila melanogaster; animal model; autophagy; neurodegeneration; non-autonomous signaling; protein-aggregate; protein-misfolding; proteinopathies
    DOI:  https://doi.org/10.3389/fnins.2023.1082047
  7. Biophys Rep. 2022 Feb 28. 8(1): 14-28
    Cellular and animal models to investigate pathogenesis of amyloid aggregation in neurodegenerative diseases.
    Houfang Long, Shuyi Zeng, Dan Li.
      Abnormal aggregation of amyloid proteins, e.g. amyloid β (Aβ), Tau and α-synuclein (α-syn), is closely associated with a variety of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Cellular and animal models are useful to explore the neuropathology of amyloid aggregates in disease initiation and progression. In this protocol, we describe detailed procedures for how to establish neuronal and PD mouse models to evaluate amyloid pathologies including self-propagation, cell-to-cell transmission, neurotoxicity, and impact on mouse motor and cognitive functions. We use α-syn, a key pathogenic protein in PD, as an example to demonstrate the application of the protocol, while it can be used to investigate the pathologies of other amyloid proteins as well. The established disease models are also useful to assess the activities of drug candidates for therapeutics of neurodegenerative diseases.
    Keywords:  Amyloid fibril; Mouse model; Parkinson’s disease; Primary neuron; α-Synuclein
    DOI:  https://doi.org/10.52601/bpr.2022.210033
  8. Science. 2023 Jun 09. 380(6649): 1010-1011
    Taurine linked with healthy aging.
    Joseph McGaunn, Joseph A Baur.
      Reversing age-associated taurine loss improves mouse longevity and monkey health.
    DOI:  https://doi.org/10.1126/science.adi3025
  9. Am J Physiol Heart Circ Physiol. 2023 Jun 09.
    mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes.
    Christoph Hofmann, Zoe Löwenthal, Marjan Aghajani, Randal J Kaufman, Hugo A Katus, Norbert Frey, Christopher C Glembotski, Mirko Völkers, Shirin Doroudgar.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of protein synthesis that senses and responds to a variety of stimuli to coordinate cellular metabolism with environmental conditions. To ensure that protein synthesis is inhibited during unfavorable conditions, translation is directly coupled to the sensing of cellular protein homeostasis. Thus, translation is attenuated during endoplasmic reticulum (ER) stress by direct inhibition of the mTORC1 pathway. However, residual mTORC1 activity is maintained during prolonged ER stress which is thought to be involved in translational reprogramming and adaption to ER stress. By analyzing the dynamics of mTORC1 regulation during ER stress, we unexpectedly found that mTORC1 is transiently activated in cardiomyocytes within minutes at the onset of ER stress before being inhibited during chronic ER stress. This dynamic regulation of mTORC1 appears to be mediated, at least in part, by ATF6, as its activation was sufficient to induce the biphasic control of mTORC1. We further showed that protein synthesis remains dependent on mTORC1 throughout the ER stress response and that mTORC1 activity is essential for posttranscriptional induction of several unfolded protein response elements. Pharmacological inhibition of mTORC1 increased cell death during ER stress, indicating that the mTORC1 pathway serves adaptive functions during ER stress in cardiomyocytes potentially by controlling the expression of the protective unfolded protein response.
    Keywords:  ATF6; ER stress; cardiomyocytes; cell death; mTORC1
    DOI:  https://doi.org/10.1152/ajpheart.00682.2022
  10. Nat Rev Mol Cell Biol. 2023 Jun 08.
    Hypoxia prevents premature ageing in mice.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-023-00626-7
  11. Neurosci Res. 2023 Jun 02. pii: S0168-0102(23)00106-2. [Epub ahead of print]
    Single-cell transcriptomics identifies perturbed molecular pathways in midbrain organoids using α-Synuclein triplication Parkinson's Disease patient-derived iPSCs.
    Nikolaos Patikas, Rizwan Ansari, Emmanouil Metzakopian.
      Three-dimensional(3D) brain organoids provide a platform to study brain development, cellular coordination, and disease using human tissue. Here, we generate midbrain dopaminergic(mDA) organoids from induced pluripotent stem cells(iPSC) from healthy and Parkinson's Disease(PD) donors and assess them as a human PD model using single-cell RNAseq. We characterize cell types in our organoid cultures and analyze our model's Dopamine (DA) neurons using cytotoxic and genetic stressors. Our study provides the first in-depth, single-cell analysis of SNCA triplication DA neurons and shows evidence for molecular dysfunction in oxidative phosphorylation, translation, and ER protein-folding in these cells. We perform an in-silico identification of rotenone-sensitive DA neurons and characterization of corresponding transcriptomic profiles associated with synaptic signalling and cholesterol biosynthesis. Finally, we show a novel chimera organoid model from healthy and PD iPSCs allowing the study of DA neurons from different individuals within the same tissue.
    Keywords:  Parkinsons Disease; SNCA; iPSC; oxidative-stress; scRNAseq; αSynuclein
    DOI:  https://doi.org/10.1016/j.neures.2023.06.001
  12. J Neurochem. 2023 Jun 07.
    BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology.
    Yanna Zhao, Hongyan Zhou, Yan Zhao, Zhen Liang, Xiaokang Gong, Jing Yu, Tiantian Huang, Chaoqin Yang, Mengjuan Wu, Yifan Xiao, Youhua Yang, Wei Liu, Xiaochuan Wang, Xiji Shu, Jian Bao.
      BACE1 is essential for the generation of amyloid-β (Aβ) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aβ accumulation.
    Keywords:  Alzheimer's disease; BACE1; SUMOylation; amyloid-β; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.1111/jnc.15870
  13. Transl Neurodegener. 2023 Jun 08. 12(1): 29
    Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases.
    Chih Hung Lo, Jialiu Zeng.
      Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Autophagy dysfunction; Early detection; Lysosomal de-acidification; Nanomedicine; Nanoparticles; Neurodegenerative diseases; Parkinson’s disease; Prognostic marker; Small molecules
    DOI:  https://doi.org/10.1186/s40035-023-00362-0
  14. J Cell Biol. 2023 Jul 03. pii: e202304011. [Epub ahead of print]222(7):
    Toward a standard model for autophagosome biogenesis.
    Annan S I Cook, James H Hurley.
      Two papers in this issue resolve a long-standing obstacle to a "standard model" for autophagosome biogenesis in mammals. The first, Olivas et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202208088), uses biochemistry to confirm that the lipid scramblase ATG9A is a bona fide autophagosome component, while the second, Broadbent et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202210078), uses particle tracking to show that the dynamics of autophagy proteins are consistent with the concept.
    DOI:  https://doi.org/10.1083/jcb.202304011
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