bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–05–29
23 papers selected by
Rich Giadone, Harvard University
  1. ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.
  2. Evidence From Human Placenta, Endoplasmic Reticulum-Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia.
  3. Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer's Disease.
  4. Protein interaction networks in neurodegenerative diseases: from physiological function to aggregation.
  5. Maintaining the thyroid gland in mutant thyroglobulin-induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood.
  6. Activating transcription factor 6 regulates cystathionine to increase autophagy and restore memory in Alzheimer' s disease model mice.
  7. Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum.
  8. The UPRmt preserves mitochondrial import to extend lifespan.
  9. Brain Extract of Subacute Traumatic Brain Injury Promotes the Neuronal Differentiation of Human Neural Stem Cells via Autophagy.
  10. A Chemical Mutagenesis Approach to Insert Post-translational Modifications in Aggregation-Prone Proteins.
  11. DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
  12. Electrostatics drive the molecular chaperone BiP to preferentially bind oligomerized states of a client protein.
  13. Neurogenesis Is Increased in Human Neural Stem Cells by Aβ40 Peptide.
  14. Coordinative regulation of ERAD and selective autophagy in plants.
  15. The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis.
  16. Advances in Recapitulating Alzheimer's Disease Phenotypes Using Human Induced Pluripotent Stem Cell-Based In Vitro Models.
  17. Hsp70 exhibits a liquid-liquid phase separation ability and chaperones condensed FUS against amyloid aggregation.
  18. Mechanisms of ER Protein Import.
  19. An Integrated Approach Reveals DNA Damage and Proteotoxic Stress as Main Effects of Proton Radiation in S. cerevisiae.
  20. Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases.
  21. Compounds for selective translational inhibition.
  22. Understanding the Human Aging Proteome Using Epidemiological Models.
  23. Cell type-specific biotin labeling in vivo resolves regional neuronal and astrocyte proteomic differences in mouse brain.
  1. Cells. 2022 May 17. pii: 1661. [Epub ahead of print]11(10):
    ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.
    Jaleh S Mesgarzadeh, Isabelle C Romine, Ethan M Smith-Cohen, Julia M D Grandjean, Jeffery W Kelly, Joseph C Genereux, R Luke Wiseman.
      The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce the toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone proteins secreted from mammalian cells. The stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases the secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass-spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions in destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent mechanism. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction in destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases.
    Keywords:  ATF6; ER proteostasis; amyloid disease; extracellular proteostasis; protein aggregation; protein disulfide isomerase (PDI); unfolded protein response (UPR)
    DOI:  https://doi.org/10.3390/cells11101661
  2. Hypertension. 2022 May 24. 101161HYPERTENSIONAHA12118916
    Evidence From Human Placenta, Endoplasmic Reticulum-Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia.
    Shibin Cheng, Zheping Huang, Sayani Banerjee, Sukanta Jash, Joel N Buxbaum, Surendra Sharma.
       BACKGROUND: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several aggregated proteins in the circulation of preeclampsia patients, the most prominent of which is the serum protein TTR (transthyretin). However, the mechanisms that underlie protein aggregation remain poorly addressed.
    METHODS: We examined TTR aggregates in hypoxia/reoxygenation-exposed primary human trophoblasts (PHTs) and the preeclampsia placenta using complementary approaches, including a novel protein aggregate detection assay. Mechanistic analysis was performed in hypoxia/reoxygenation-exposed PHTs and Ttr transgenic mice overexpressing transgene-encoded wild-type human TTR or Ttr-/- mice. High-resolution ultrasound analysis was used to measure placental blood flow in pregnant mice.
    RESULTS: TTR aggregation was inducible in PHTs and the TCL-1 trophoblast cell line by endoplasmic reticulum stress inducers or autophagy-lysosomal disruptors. PHTs exposed to hypoxia/reoxygenation showed increased intracellular BiP (binding immunoglobulin protein), phosphorylated IRE1α (inositol-requiring enzyme-1α), PDI (protein disulfide isomerase), and Ero-1, all markers of the unfolded protein response, and the apoptosis mediator caspase-3. Blockade of IRE1α inhibited hypoxia/reoxygenation-induced upregulation of Ero-1 in PHTs. Excessive unfolded protein response activation was observed in the early-onset preeclampsia placenta. Importantly, pregnant human TTR mice displayed aggregated TTR in the junctional zone of the placenta and severe preeclampsia-like features. High-resolution ultrasound analysis revealed low blood flow in uterine and umbilical arteries in human TTR mice compared with control mice. However, Ttr-/- mice did not show any pregnancy-associated abnormalities.
    CONCLUSIONS: These observations in the preeclampsia placenta, cultured trophoblasts, and Ttr transgenic mice indicate that TTR aggregation is an important causal contributor to preeclampsia pathophysiology.
    Keywords:  autophagy; endoplasmic reticulum stress; lysosomes; placenta; unfolded protein response
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.121.18916
  3. Front Aging Neurosci. 2022 ;14 880167
    Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer's Disease.
    Nusrath Yasmeen, Manali Datta, Vikram Kumar, Fahad S Alshehri, Atiah H Almalki, Shafiul Haque.
      Alzheimer's disease (AD) is a neurodegenerative proteinopathic disease. The deposits of misfolded Amyloid β and Tau proteins in the brain of patients with AD suggest an imbalance in endoplasmic reticulum (ER) proteostasis. ER stress is due to accumulation of aberrant proteins in the ER lumen, which then leads to activation of three sensor protein pathways that ultimately evokes the adaptive mechanism of the unfolded protein response (UPR). The UPR mechanism operates via adaptive UPR and the apoptotic UPR. Adaptive UPR tries to restore imbalance in ER hemostasis by decreasing protein production, enhanced chaperone involvement to restore protein folding, misfolded protein decay by proteasome, and suppression of ribosomal translation ultimately relieving the excessive protein load in the ER. Subsequently, apoptotic UPR activated under severe ER stress conditions triggers cell death. MicroRNAs (miRNAs) are small non-coding protein causing dysregulated translational of mRNAs in a sequential manner. They are considered to be critical elements in the maintenance of numerous cellular activities, hemostasis, and developmental processes. Therefore, upregulation or downregulation of miRNA expression is implicated in several pathogenic processes. Evidence from scientific studies suggest a strong correlation between ERUPR signaling and miRNA dysregulation but the research done is still dormant. In this review, we summarized the cross-talk between ER stress, and the UPR signaling processes and their role in AD pathology by scrutinizing and collecting information from original research and review articles.
    Keywords:  Alzheimer’s disease; ER stress; microRNA; neurodegeneration; unfolded protein response (UPR)
    DOI:  https://doi.org/10.3389/fnagi.2022.880167
  4. J Biol Chem. 2022 May 24. pii: S0021-9258(22)00502-6. [Epub ahead of print] 102062
    Protein interaction networks in neurodegenerative diseases: from physiological function to aggregation.
    Gaetano Calabrese, Cristen Molzahn, Thibault Mayor.
      The accumulation of protein inclusions is linked to many neurodegenerative diseases that typically develop in older individuals, due to a combination of genetic and environmental factors. In rare familial neurodegenerative disorders, genes encoding for aggregation-prone proteins are often mutated. While the underlying mechanism leading to these diseases still remains to be fully elucidated, efforts in the past twenty years revealed a vast network of protein-protein interactions that play a major role in regulating the aggregation of key proteins associated with neurodegeneration. Misfolded proteins that can oligomerize and form insoluble aggregates associate with molecular chaperones and other elements of the proteolytic machineries that are the front-line workers attempting to protect the cells by promoting clearance and preventing aggregation. Proteins that are normally bound to aggregation-prone proteins can become sequestered and mislocalized in protein inclusions, leading to their loss of function. In contrast, mutations, post-translational modifications or misfolding of aggregation-prone proteins can lead to gain of function by inducing novel or altered protein interactions, which in turn can impact numerous essential cellular processes and organelles, such as vesicle trafficking and the mitochondria. This review examines our current knowledge of protein-protein interactions involving several key aggregation-prone proteins that are associated with Alzheimer's disease, Parkinson's disease, Huntington's disease or amyotrophic lateral sclerosis. We aim to provide an overview of the protein interaction networks that play a central role in driving or mitigating inclusion formation, while highlighting some of the key proteomic studies that helped to uncover the extent of these networks.
    Keywords:  ALS; Alzheimer; Huntington; Parkinson; amyloid; chaperone; misfolding; mitochondria; neurodegenerative disease; protein aggregation; protein interaction network; proteolysis; proteomics; ubiquitin proteasome system
    DOI:  https://doi.org/10.1016/j.jbc.2022.102062
  5. J Biol Chem. 2022 May 23. pii: S0021-9258(22)00506-3. [Epub ahead of print] 102066
    Maintaining the thyroid gland in mutant thyroglobulin-induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood.
    Xiaohan Zhang, Bhoomanyu Malik, Crystal Young, Hao Zhang, Dennis Larkin, Xiao-Hui Liao, Samuel Refetoff, Ming Liu, Peter Arvan.
      Congenital hypothyroidism with biallelic thyroglobulin mutation is an endoplasmic reticulum (ER) storage disease. Many patients (and animal models) grow an enlarged thyroid (goiter), yet some do not. In adulthood, hypothyroid TGcog/cog mice (bearing a Tg-L2263P mutation) exhibit a large goiter, whereas adult WIC rats bearing the TGrdw/rdw mutation (Tg-G2298R) exhibit a hypoplastic thyroid. Homozygous TG mutation has been linked to thyroid cell death, and cytotoxicity of the Tg-G2298R protein was previously thought to explain the lack of goiter in WIC-TGrdw/rdw rats. However, recent studies revealed that TGcog/cog mice also exhibit widespread ER stress-mediated thyrocyte death, yet under continuous feedback stimulation thyroid cells proliferate in excess of their demise. Here, to examine the relative proteotoxicity of the Tg-G2298R protein, we've used CRISPR/Cas9 technology to generate homozygous TGrdw/rdw knock-in mice in a strain background identical to that of TGcog/cog mice. TGrdw/rdw mice exhibit similar phenotypes of defective Tg protein folding, thyroid histological abnormalities, hypothyroidism, and growth retardation. TGrdw/rdw mice do not show evidence of greater ER stress response or stress-mediated cell death than TGcog/cog mice, and both mouse models exhibit sustained thyrocyte proliferation, with comparable goiter growth. In contrast, in WIC-TGrdw/rdw rats, as a function of aging, the thyrocyte proliferation rate declines precipitously. We conclude that the mutant Tg-G2298R protein is not intrinsically more proteotoxic than Tg-L2263P; rather, aging-dependent differences in maintenance of cell proliferation is the limiting factor, which accounts for absence of goiter in adult WIC-TGrdw/rdw rats.
    Keywords:  ER stress; aging; cell death; protein misfolding; secretory pathway
    DOI:  https://doi.org/10.1016/j.jbc.2022.102066
  6. Biochem Biophys Res Commun. 2022 May 17. pii: S0006-291X(22)00751-3. [Epub ahead of print]615 109-115
    Activating transcription factor 6 regulates cystathionine to increase autophagy and restore memory in Alzheimer' s disease model mice.
    Jun-Yuan Zhang, Shuang Ma, Xiaoli Liu, Yayun Du, Xilin Zhu, Ying Liu, Xiaopan Wu.
      Endoplasmic reticulum stress (ER stress) plays a crucial role in the process of Alzheimer's disease (AD). Activating transcription factor 6 (ATF6) is a crucial sensor of ER stress. In AD patients, the homeostasis of the endogenous signal H2S produced by cystathionine γ-lyase (CTH) is in disbalance. However, the role of ATF6 and CTH in AD is rarely reported. Herein, we found that ATF6 and CTH were reduced in AD patients and APP/PS1 mice by immunohistochemistry and western blots. In LN229 and U87 MG cells, knockdown of ATF6 attenuated CTH expression, whereas overexpression of ATF6 resulted in upregulation of CTH. Brain-specific ATF6 knockout mice expressed significantly down-regulated CTH in the hippocampus and cortex compared to wild-type mice. Mechanistically, ATF6 and CTH increased H2S generation and autophagy-related proteins. Further we observed that CTH promoted the sulfhydration of αSNAP. This is probably to be the specific mechanism by which AFT6 promotes autophagy. Through in vivo studies, we found that αSNAP sulfhydration expression was significantly lower in ATF6 knockout mice than in wild-type mice. Decreased ATF6 impaired spatial memory retention, while addition of CTH rescued memory loss. Together, we demonstrate that ATF6 positively regulates the expression of CTH, which is closely related to the rescue of AD. Targeting the ATF6/CTH signal pathway may provide a new strategy for the treatment of AD.
    Keywords:  Activating transcription factor 6; Alzheimer's disease; Autophagy; Cystathionine γ-lyase; H(2)S
    DOI:  https://doi.org/10.1016/j.bbrc.2022.05.053
  7. Int J Mol Sci. 2022 May 17. pii: 5576. [Epub ahead of print]23(10):
    Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum.
    Lea Daverkausen-Fischer, Margarethe Draga, Felicitas Pröls.
      The endoplasmic reticulum (ER) of mammalian cells is the central organelle for the maturation and folding of transmembrane proteins and for proteins destined to be secreted into the extracellular space. The proper folding of target proteins is achieved and supervised by a complex endogenous chaperone machinery. BiP, a member of the Hsp70 protein family, is the central chaperone in the ER. The chaperoning activity of BiP is assisted by ER-resident DnaJ (ERdj) proteins due to their ability to stimulate the low, intrinsic ATPase activity of BiP. Besides their co-chaperoning activity, ERdj proteins also regulate and tightly control the translation, translocation, and degradation of proteins. Disturbances in the luminal homeostasis result in the accumulation of unfolded proteins, thereby eliciting a stress response, the so-called unfolded protein response (UPR). Accumulated proteins are either deleterious due to the functional loss of the respective protein and/or due to their deposition as intra- or extracellular protein aggregates. A variety of metabolic diseases are known to date, which are associated with the dysfunction of components of the chaperone machinery. In this review, we will delineate the impact of ERdj proteins in controlling protein synthesis and translocation under physiological and under stress conditions. A second aspect of this review is dedicated to the role of ERdj proteins in the ER-associated degradation pathway, by which unfolded or misfolded proteins are discharged from the ER. We will refer to some of the most prominent diseases known to be based on the dysfunction of ERdj proteins.
    Keywords:  ERAD; UPR; co-chaperones; degradation; translocation; translocon
    DOI:  https://doi.org/10.3390/ijms23105576
  8. J Cell Biol. 2022 Jul 04. pii: e202201071. [Epub ahead of print]221(7):
    The UPRmt preserves mitochondrial import to extend lifespan.
    Nan Xin, Jenni Durieux, Chunxia Yang, Suzanne Wolff, Hyun-Eui Kim, Andrew Dillin.
      The mitochondrial unfolded protein response (UPRmt) is dedicated to promoting mitochondrial proteostasis and is linked to extreme longevity. The key regulator of this process is the transcription factor ATFS-1, which, upon UPRmt activation, is excluded from the mitochondria and enters the nucleus to regulate UPRmt genes. However, the repair proteins synthesized as a direct result of UPRmt activation must be transported into damaged mitochondria that had previously excluded ATFS-1 owing to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery when the UPRmt was induced. Using in vitro and in vivo analysis of mitochondrial proteins, we surprisingly find that mitochondrial import increases when the UPRmt is activated in an ATFS-1-dependent manner, despite reduced mitochondrial membrane potential. The import machinery is upregulated, and an intact import machinery is essential for UPRmt-mediated lifespan extension. ATFS-1 has a weak mitochondrial targeting sequence (MTS), allowing for dynamic subcellular localization during the initial stages of UPRmt activation.
    DOI:  https://doi.org/10.1083/jcb.202201071
  9. J Clin Med. 2022 May 11. pii: 2709. [Epub ahead of print]11(10):
    Brain Extract of Subacute Traumatic Brain Injury Promotes the Neuronal Differentiation of Human Neural Stem Cells via Autophagy.
    Zhenghui He, Lijian Lang, Jiyuan Hui, Yuxiao Ma, Chun Yang, Weiji Weng, Jialin Huang, Xiongfei Zhao, Xiaoqi Zhang, Qian Liang, Jiyao Jiang, Junfeng Feng.
       BACKGROUND: After a traumatic brain injury (TBI), the cell environment is dramatically changed, which has various influences on grafted neural stem cells (NSCs). At present, these influences on NSCs have not been fully elucidated, which hinders the finding of an optimal timepoint for NSC transplantation.
    METHODS: Brain extracts of TBI mice were used in vitro to simulate the different phase TBI influences on the differentiation of human NSCs. Protein profiles of brain extracts were analyzed. Neuronal differentiation and the activation of autophagy and the WNT/CTNNB pathway were detected after brain extract treatment.
    RESULTS: Under subacute TBI brain extract conditions, the neuronal differentiation of hNSCs was significantly higher than that under acute brain extract conditions. The autophagy flux and WNT/CTNNB pathway were activated more highly within the subacute brain extract than in the acute brain extract. Autophagy activation by rapamycin could rescue the neuronal differentiation of hNSCs within acute TBI brain extract.
    CONCLUSIONS: The subacute phase around 7 days after TBI in mice could be a candidate timepoint to encourage more neuronal differentiation after transplantation. The autophagy flux played a critical role in regulating neuronal differentiation of hNSCs and could serve as a potential target to improve the efficacy of transplantation in the early phase.
    Keywords:  autophagy; differentiation; neural stem cells; traumatic brain injury
    DOI:  https://doi.org/10.3390/jcm11102709
  10. ACS Chem Neurosci. 2022 May 24.
    A Chemical Mutagenesis Approach to Insert Post-translational Modifications in Aggregation-Prone Proteins.
    Ying Ge, Athina Masoura, Jingzhou Yang, Francesco A Aprile.
      Neurodegenerative diseases are a class of disorders linked to the formation in the nervous system of fibrillar protein aggregates called amyloids. This aggregation process is affected by a variety of post-translational modifications, whose specific mechanisms are not fully understood yet. Emerging chemical mutagenesis technology is currently striving to address the challenge of introducing protein post-translational modifications, while maintaining the stability and solubility of the proteins during the modification reaction. Several amyloidogenic proteins are highly aggregation-prone, and current modification procedures can lead to unexpected precipitation of these proteins, affecting their yield and downstream characterization. Here, we present a method for maintaining amyloidogenic protein solubility during chemical mutagenesis. As proof-of-principle, we applied our method to mimic the phosphorylation of serine-26 and the acetylation of lysine-28 of the 40-residue long variant of amyloid-β peptide, whose aggregation is linked to Alzheimer's disease.
    Keywords:  Alzheimer’s disease; amyloid-β; chemical mutagenesis; post-translational modification
    DOI:  https://doi.org/10.1021/acschemneuro.2c00077
  11. Dev Cell. 2022 May 15. pii: S1534-5807(22)00306-9. [Epub ahead of print]
    DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
    Barbara Pernaute, Salvador Pérez-Montero, Juan Miguel Sánchez Nieto, Aida Di Gregorio, Ana Lima, Katerina Lawlor, Sarah Bowling, Gianmaria Liccardi, Alejandra Tomás, Pascal Meier, Hiromi Sesaki, Guy A Rutter, Ivana Barbaric, Tristan A Rodríguez.
      The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.
    Keywords:  apoptosis; early development; embryonic stem cell differentiation; mitochondrial dynamics; mitophagy; pluripotency
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.020
  12. J Mol Biol. 2022 May 18. pii: S0022-2836(22)00218-2. [Epub ahead of print] 167638
    Electrostatics drive the molecular chaperone BiP to preferentially bind oligomerized states of a client protein.
    Erin E Deans, Judy L M Kotler, Wei-Shao Wei, Timothy O Street.
      Hsp70 chaperones bind short monomeric peptides with a weak characteristic affinity in the low micromolar range, but can also bind some aggregates, fibrils, and amyloids, with low nanomolar affinity. While this differential affinity enables Hsp70 to preferentially target potentially toxic aggregates, it is unknown how a chaperone can differentiate between monomeric and aggregated states of a client protein and why preferential binding is only observed for some aggregated clients but not others. Here we examine the interaction of BiP (the Hsp70 paralog in the endoplasmic reticulum) with the client proIGF2, the pro-protein form of IGF2 that includes a long and mostly disordered E-peptide region that promotes proIGF2 oligomerization. By dissecting the mechanism by which BiP targets proIGF2 and E-peptide oligomers we discover that electrostatic attraction is a powerful driving force for oligomer recognition. We identify the specific BiP binding sites on proIGF2 and as monomers they bind BiP with characteristically weak affinity in the low micromolar range, but electrostatic attraction to E-peptide oligomers boosts the affinity to the low nanomolar level. The dominant role of electrostatics is manifested kinetically as a steering force that accelerates the binding of BiP to E-peptide oligomers by approximately two orders of magnitude as compared against monomeric peptides. Electrostatic targeting of Hsp70 provides an explanation for why preferential binding has been observed for some aggregated clients but not others, as all the currently-documented cases in which Hsp70 binds aggregates with high-affinity involve clients that have an opposite charge to Hsp70.
    DOI:  https://doi.org/10.1016/j.jmb.2022.167638
  13. Int J Mol Sci. 2022 May 22. pii: 5820. [Epub ahead of print]23(10):
    Neurogenesis Is Increased in Human Neural Stem Cells by Aβ40 Peptide.
    Adela Bernabeu-Zornoza, Raquel Coronel, Charlotte Palmer, Alberto Martín, Victoria López-Alonso, Isabel Liste.
      Amyloid-β 40 peptides [Aβ1-40 (Aβ40)] are present within amyloid plaques in the brains of patients with Alzheimer's disease (AD). Even though Aβ peptides are considered neurotoxic, they can mediate many biological processes, both in adult brains and throughout brain development. However, the physiological function of these Aβ peptides remains poorly understood, and the existing data are sometimes controversial. Here, we analyze and compare the effects of monomeric Aβ40 on the biology of differentiating human neural stem cells (human NSCs). For that purpose, we used a model of human NSCs called hNS1. Our data demonstrated that Aβ40 at high concentrations provokes apoptotic cellular death and the damage of DNA in human NSCs while also increasing the proliferation and favors neurogenesis by raising the percentage of proliferating neuronal precursors. These effects can be mediated, at least in part, by β-catenin. These results provide evidence of how Aβ modulate/regulate human NSC proliferation and differentiation, suggesting Aβ40 may be a pro-neurogenic factor. Our data could contribute to a better understanding of the molecular mechanisms involved in AD pathology and to the development of human NSC-based therapies for AD treatment, since these results could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.
    Keywords:  Alzheimer’s; Aβ40; cell proliferation; human neural stem cells; neurogenesis
    DOI:  https://doi.org/10.3390/ijms23105820
  14. Essays Biochem. 2022 May 25. pii: EBC20210099. [Epub ahead of print]
    Coordinative regulation of ERAD and selective autophagy in plants.
    Qian Chen, Yaorong Wu, Feifei Yu, Qi Xie.
      Endoplasmic reticulum-associated degradation (ERAD) plays important roles in plant development, hormone signaling, and plant-environment stress interactions by promoting the clearance of certain proteins or soluble misfolded proteins through the ubiquitin-proteasome system. Selective autophagy is involved in the autophagic degradation of protein aggregates mediated by specific selective autophagy receptors. These two major degradation routes co-operate with each other to relieve the cytotoxicity caused by ER stress. In this review, we analyze ERAD and different types of autophagy, including nonselective macroautophagy and ubiquitin-dependent and ubiquitin-independent selective autophagy in plants, and specifically summarize the selective autophagy receptors characterized in plants. In addition to being a part of selective autophagy, ERAD components also serve as their cargos. Moreover, an ubiquitinated substrate can be delivered to two distinguishable degradation systems, while the underlying determinants remain elusive. These excellent findings suggest an interdependent but complicated relationship between ERAD and selective autophagy. According to this point, we propose several key issues that need to be addressed in the future.
    Keywords:  ERAD; plant biology; protein degradation; selective autophagy
    DOI:  https://doi.org/10.1042/EBC20210099
  15. Proc Natl Acad Sci U S A. 2022 May 31. 119(22): e2200468119
    The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis.
    N Guthertz, R van der Kant, R M Martinez, Y Xu, C Trinh, B I Iorga, F Rousseau, J Schymkowitz, D J Brockwell, S E Radford.
      SignificanceProtein aggregation is a major problem for human health. However, our understanding of how folded proteins aggregate into amyloid lags behind. Using the tripartite β-lactamase assay (TPBLA) with our test protein, β2-microglobulin (β2m), we show the ability to differentiate the behavior of single-point variants and highlight the remarkable sensitivity to the identity of the residue at position 76. After evolving the aggregation-prone protein, D76N-β2m, the only mutations able to improve D76N-β2m behavior in vivo involve residues in a single 7-residue sequence of the protein. Further characterization in vitro shows that a single-point mutant in this region can abolish D76N-β2m aggregation.
    Keywords:  aggregation; amyloid; evolution
    DOI:  https://doi.org/10.1073/pnas.2200468119
  16. Brain Sci. 2022 Apr 26. pii: 552. [Epub ahead of print]12(5):
    Advances in Recapitulating Alzheimer's Disease Phenotypes Using Human Induced Pluripotent Stem Cell-Based In Vitro Models.
    Md Fayad Hasan, Eugenia Trushina.
      Alzheimer's disease (AD) is an incurable neurodegenerative disorder and the leading cause of death among older individuals. Available treatment strategies only temporarily mitigate symptoms without modifying disease progression. Recent studies revealed the multifaceted neurobiology of AD and shifted the target of drug development. Established animal models of AD are mostly tailored to yield a subset of disease phenotypes, which do not recapitulate the complexity of sporadic late-onset AD, the most common form of the disease. The use of human induced pluripotent stem cells (HiPSCs) offers unique opportunities to fill these gaps. Emerging technology allows the development of disease models that recapitulate a brain-like microenvironment using patient-derived cells. These models retain the individual's unraveled genetic background, yielding clinically relevant disease phenotypes and enabling cost-effective, high-throughput studies for drug discovery. Here, we review the development of various HiPSC-based models to study AD mechanisms and their application in drug discovery.
    Keywords:  3D culture; Alzheimer’s disease; biofabrication; disease modeling; human induced pluripotent stem cell (HiPSC); microfluidics; organoid; spheroid; stem cells
    DOI:  https://doi.org/10.3390/brainsci12050552
  17. iScience. 2022 Jun 17. 25(6): 104356
    Hsp70 exhibits a liquid-liquid phase separation ability and chaperones condensed FUS against amyloid aggregation.
    Yichen Li, Jinge Gu, Chen Wang, Jiaojiao Hu, Shenqing Zhang, Cong Liu, Shengnan Zhang, Yanshan Fang, Dan Li.
      Hsp70 is a key molecular chaperone in the protein quality control system to safeguard protein homeostasis in cells. Previous studies have shown that Hsp70 chaperones TDP-43, a pathogenic protein associated with amyotrophic lateral sclerosis (ALS), in nuclear bodies and prevents it from the pathological aggregation. In this work, we report that Hsp70 undergoes liquid-liquid phase separation, chaperones FUS, another ALS-linked pathogenic protein, in stress granules (SGs), and prevents condensed FUS from amyloid aggregation. Knock-down of Hsp70 does not influence SG assembly but results in the liquid-to-solid transition in SGs. NMR experiments further reveal Hsp70 predominantly uses its C-terminal substrate-binding domain to interact with the low complexity domain of FUS, which represents a mechanism distinct from that interacting with TDP-43. These findings suggest that Hsp70 is widely involved in chaperoning the physiological dynamics of various membrane-less organelles and adopts different mechanisms to prevent the pathological aggregation of different proteins.
    Keywords:  Biophysical chemistry; Biophysics; Cell biology; Organizational aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104356
  18. Int J Mol Sci. 2022 May 10. pii: 5315. [Epub ahead of print]23(10):
    Mechanisms of ER Protein Import.
    Sven Lang, Richard Zimmermann.
      Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of approximately 10,000 different soluble and membrane proteins of human cells, which amounts to about 30% of the proteome [...].
    DOI:  https://doi.org/10.3390/ijms23105315
  19. Int J Mol Sci. 2022 May 14. pii: 5493. [Epub ahead of print]23(10):
    An Integrated Approach Reveals DNA Damage and Proteotoxic Stress as Main Effects of Proton Radiation in S. cerevisiae.
    Laura Vanderwaeren, Rüveyda Dok, Karin Voordeckers, Laura Vandemaele, Kevin J Verstrepen, Sandra Nuyts.
      Proton radiotherapy (PRT) has the potential to reduce the normal tissue toxicity associated with conventional photon-based radiotherapy (X-ray therapy, XRT) because the active dose can be more directly targeted to a tumor. Although this dosimetric advantage of PRT is well known, the molecular mechanisms affected by PRT remain largely elusive. Here, we combined the molecular toolbox of the eukaryotic model Saccharomyces cerevisiae with a systems biology approach to investigate the physiological effects of PRT compared to XRT. Our data show that the DNA damage response and protein stress response are the major molecular mechanisms activated after both PRT and XRT. However, RNA-Seq revealed that PRT treatment evoked a stronger activation of genes involved in the response to proteotoxic stress, highlighting the molecular differences between PRT and XRT. Moreover, inhibition of the proteasome resulted in decreased survival in combination with PRT compared to XRT, not only further confirming that protons induced a stronger proteotoxic stress response, but also hinting at the potential of using proteasome inhibitors in combination with proton radiotherapy in clinical settings.
    Keywords:  DNA damage response; proteotoxic stress; proton radiation; radiobiology; radiotherapy
    DOI:  https://doi.org/10.3390/ijms23105493
  20. Front Aging Neurosci. 2022 ;14 845330
    Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases.
    Wei Wan, Fuzhou Hua, Pu Fang, Chang Li, Fumou Deng, Shoulin Chen, Jun Ying, Xifeng Wang.
      Sirtuins are protein factors that can delay aging and alleviate age-related diseases through multiple molecular pathways, mainly by promoting DNA damage repair, delaying telomere shortening, and mediating the longevity effect of caloric restriction. In the last decade, sirtuins have also been suggested to exert mitochondrial quality control by mediating mitophagy, which targets damaged mitochondria and delivers them to lysosomes for degradation. This is especially significant for age-related diseases because dysfunctional mitochondria accumulate in aging organisms. Accordingly, it has been suggested that sirtuins and mitophagy have many common and interactive aspects in the aging process. This article reviews the mechanisms and pathways of sirtuin family-mediated mitophagy and further discusses its role in aging and age-related diseases.
    Keywords:  age-related disease; aging; mitochondria; mitophagy; neurodegenerative diseases; sirtuins
    DOI:  https://doi.org/10.3389/fnagi.2022.845330
  21. Curr Opin Chem Biol. 2022 May 19. pii: S1367-5931(22)00043-6. [Epub ahead of print]69 102158
    Compounds for selective translational inhibition.
    Yuichi Shichino, Shintaro Iwasaki.
      Since many human diseases are caused by the unwelcome production of harmful proteins, compounds that selectively suppress protein synthesis should provide a unique path for drug development, expanding the druggable proteome. Although surveying the RNA/amino acid contexts that are preferentially affected by translation inhibitors has presented an analytic hurdle, the application of a technique termed ribosome profiling overcomes this problem. Indeed, this technique uncovers the selectivity of translation repression by small molecules such as chloramphenicol, macrolides, PF846, and rocaglates. The molecular understanding of how the compounds inspire context selectivity, despite their targeting to general translation machinery, facilitates rational drug design and discovery for therapeutic purposes.
    DOI:  https://doi.org/10.1016/j.cbpa.2022.102158
  22. Methods Mol Biol. 2022 ;2399 173-192
    Understanding the Human Aging Proteome Using Epidemiological Models.
    Ceereena Ubaida-Mohien, Ruin Moaddel, Zenobia Moore, Pei-Lun Kuo, Ravi Tharakan, Toshiko Tanaka, Luigi Ferrucci.
      Human aging is a complex multifactorial process associated with a decline of physical and cognitive function and high susceptibility to chronic diseases, influenced by genetic, epigenetic, environmental, and demographic factors. This chapter will provide an overview on the use of epidemiological models with proteomics data as a method that can be used to identify factors that modulate the aging process in humans. This is demonstrated with proteomics data from human plasma and skeletal muscle, where the combination with epidemiological models identified a set of mitochondrial, spliceosome, and senescence proteins as well as the role of energetic pathways such as glycolysis, and electron transport pathways that regulate the aging process.
    Keywords:  Aging; BLSA; Data model; Epidemiology; GESTALT; Plasma; Proteomics; SOMAscan; Skeletal muscle; TMT
    DOI:  https://doi.org/10.1007/978-1-0716-1831-8_8
  23. Nat Commun. 2022 May 25. 13(1): 2927
    Cell type-specific biotin labeling in vivo resolves regional neuronal and astrocyte proteomic differences in mouse brain.
    Sruti Rayaprolu, Sara Bitarafan, Juliet V Santiago, Ranjita Betarbet, Sydney Sunna, Lihong Cheng, Hailian Xiao, Ruth S Nelson, Prateek Kumar, Pritha Bagchi, Duc M Duong, Annie M Goettemoeller, Viktor János Oláh, Matt Rowan, Allan I Levey, Levi B Wood, Nicholas T Seyfried, Srikant Rangaraju.
      Proteomic profiling of brain cell types using isolation-based strategies pose limitations in resolving cellular phenotypes representative of their native state. We describe a mouse line for cell type-specific expression of biotin ligase TurboID, for in vivo biotinylation of proteins. Using adenoviral and transgenic approaches to label neurons, we show robust protein biotinylation in neuronal soma and axons throughout the brain, allowing quantitation of over 2000 neuron-derived proteins spanning synaptic proteins, transporters, ion channels and disease-relevant druggable targets. Next, we contrast Camk2a-neuron and Aldh1l1-astrocyte proteomes and identify brain region-specific proteomic differences within both cell types, some of which might potentially underlie the selective vulnerability to neurological diseases. Leveraging the cellular specificity of proteomic labeling, we apply an antibody-based approach to uncover differences in neuron and astrocyte-derived signaling phospho-proteins and cytokines. This approach will facilitate the characterization of cell-type specific proteomes in a diverse number of tissues under both physiological and pathological states.
    DOI:  https://doi.org/10.1038/s41467-022-30623-x
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