bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–10–30
nineteen papers selected by
Rich Giadone, Harvard University
  1. Targeting small heat shock proteins to degrade aggregates as a potential strategy in neurodegenerative diseases.
  2. Lipids uniquely alter rates of insulin aggregation and lower toxicity of amyloid aggregates.
  3. Unfolded protein response in balancing plant growth and stress tolerance.
  4. Mitophagy in the aging nervous system.
  5. Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms.
  6. Dual role of IRE1α-XBP1 signaling in neurodegenerative diseases.
  7. Heat-Induced Proteotoxic Stress Response in Placenta-Derived Stem Cells (PDSCs) Is Mediated through HSPA1A and HSPA1B with a Potential Higher Role for HSPA1B.
  8. Calreticulin surface presentation can promote quality control of hematopoietic stem cells.
  9. Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention.
  10. CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states.
  11. Chaperoning activity of the cyclophilin family prevents tau aggregation.
  12. The mechanisms and roles of selective autophagy in mammals.
  13. A big step toward mirror-image ribosomes.
  14. Editorial: Apoptosis, autophagy, and mitophagy dysfunction in Alzheimer's disease: Evolving emergence and mechanisms.
  15. Therapeutic Antiaging Strategies.
  16. Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan.
  17. An Alzheimer's Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition.
  18. ATP13A1 prevents ERAD of folding-competent mislocalized and misoriented proteins.
  19. ER-phagy Is Involved in the Degradation of Collagen I by IL-1β in Human Amnion in Parturition.
  1. Ageing Res Rev. 2022 Oct 22. pii: S1568-1637(22)00211-2. [Epub ahead of print] 101769
    Targeting small heat shock proteins to degrade aggregates as a potential strategy in neurodegenerative diseases.
    Tong Lei, Zhuangzhuang Xiao, Wangyu Bi, Shanglin Cai, Yanjie Yang, Hongwu Du.
      Neurodegenerative diseases (NDs) are aging-related diseases that involve the death of neurons in the brain. Dysregulation of protein homeostasis leads to the production of toxic proteins or the formation of aggregates, which is the pathological basis of NDs. Small heat shock proteins (HSPB) is involved in the establishment of a protein quality control (PQC) system to maintain cellular homeostasis. HSPB can be secreted into the extracellular space and delivered by various routes, especially extracellular vehicles (EVs). HSPB plays an important role in influencing the aggregation phase of toxic proteins involved in heat shock transcription factor (HSF) regulation, oxidative stress, autophagy and apoptosis pathways. HSPB conferred neuroprotective effects by resisting toxic protein aggregation, reducing autophagy and reducing neuronal apoptosis. The HSPB treatment strategies, including targeted PQC system therapy and delivery of EVs-HSPB, can improve disease manifestations for NDs. This review aims to provide a comprehensive insight into the impact of HSPB in NDs and the feasibility of new technology to enhance HSPB expression and EVs-HSPB delivery for neurodegenerative disease.
    Keywords:  Apoptosis; Autophagy; Extracellular vesicles; PROTAC; Protein aggregation; Small heat shock proteins
    DOI:  https://doi.org/10.1016/j.arr.2022.101769
  2. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Oct 20. pii: S1388-1981(22)00137-8. [Epub ahead of print]1868(1): 159247
    Lipids uniquely alter rates of insulin aggregation and lower toxicity of amyloid aggregates.
    Mikhail Matveyenka, Stanislav Rizevsky, Jean-Philippe Pellois, Dmitry Kurouski.
      Amyloid formation is a hallmark of many medical diseases including diabetes type 2, Alzheimer's and Parkinson diseases. Under these pathological conditions, misfolded proteins self-assemble forming oligomers and fibrils, structurally heterogeneous aggregates that exhibit a large variety of shapes and forms. A growing body of evidence points to drastic changes in the lipid profile in organs affected by amyloidogenic diseases. In this study, we investigated the extent to which individual phospho- and sphingolipids, as well as their mixtures can impact insulin aggregation. Our results show that lipids and their mixtures uniquely alter rates of insulin aggregation simultaneously changing the secondary structure of protein aggregates that are grown in their presence. These structurally different protein-lipid aggregates impact cell viability to different extent while using distinct mechanisms of toxicity. These findings suggest that irreversible changes in lipid profiles of organs may trigger formation of toxic protein species that in turn are responsible for the onset and progression of amyloidogenic diseases.
    Keywords:  Atomic force microscopy; Infrared spectroscopy; Neurodegenerative disorders; Protein aggregation; Single-molecule biophysics
    DOI:  https://doi.org/10.1016/j.bbalip.2022.159247
  3. Front Plant Sci. 2022 ;13 1019414
    Unfolded protein response in balancing plant growth and stress tolerance.
    Yao Liu, Yonglun Lv, An Wei, Mujin Guo, Yanjie Li, Jiaojiao Wang, Xinhua Wang, Yan Bao.
      The ER (endoplasmic reticulum) is the largest membrane-bound multifunctional organelle in eukaryotic cells, serving particularly important in protein synthesis, modification, folding and transport. UPR (unfolded protein response) is one of the systematized strategies that eukaryotic cells employ for responding to ER stress, a condition represents the processing capability of ER is overwhelmed and stressed. UPR is usually triggered when the protein folding capacity of ER is overloaded, and indeed, mounting studies were focused on the stress responding side of UPR. In plants, beyond stress response, accumulating evidence suggests that UPR is essential for growth and development, and more importantly, the necessity of UPR in this regard requires its endogenous basal activation even without stress. Then plants must have to fine tune the activation level of UPR pathway for balancing growth and stress response. In this review, we summarized the recent progresses in plant UPR, centering on its role in controlling plant reproduction and root growth, and lay out some outstanding questions to be addressed in the future.
    Keywords:  ER stress; IRE1; UPR – unfolded protein response; bZIP; pollen; root
    DOI:  https://doi.org/10.3389/fpls.2022.1019414
  4. Front Cell Dev Biol. 2022 ;10 978142
    Mitophagy in the aging nervous system.
    Anna Rappe, Thomas G McWilliams.
      Aging is characterised by the progressive accumulation of cellular dysfunction, stress, and inflammation. A large body of evidence implicates mitochondrial dysfunction as a cause or consequence of age-related diseases including metabolic disorders, neuropathies, various forms of cancer and neurodegenerative diseases. Because neurons have high metabolic demands and cannot divide, they are especially vulnerable to mitochondrial dysfunction which promotes cell dysfunction and cytotoxicity. Mitophagy neutralises mitochondrial dysfunction, providing an adaptive quality control strategy that sustains metabolic homeostasis. Mitophagy has been extensively studied as an inducible stress response in cultured cells and short-lived model organisms. In contrast, our understanding of physiological mitophagy in mammalian aging remains extremely limited, particularly in the nervous system. The recent profiling of mitophagy reporter mice has revealed variegated vistas of steady-state mitochondrial destruction across different tissues. The discovery of patients with congenital autophagy deficiency provokes further intrigue into the mechanisms that underpin neural integrity. These dimensions have considerable implications for targeting mitophagy and other degradative pathways in age-related neurological disease.
    Keywords:  aging; autophagy; brain; disease; longevity; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2022.978142
  5. Cell Mol Life Sci. 2022 Oct 29. 79(11): 574
    Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms.
    Mariusz Karbowski, Yumiko Oshima, Nicolas Verhoeven.
      Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline. Various quality control pathways, such as mitochondrial unfolded protein response (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy), respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria. This work provides a concise review of mechanisms by which disease-linked aberrant proteins affect mitochondrial function and an overview of mitochondrial quality control pathways that counteract mitochondrial proteotoxicity. We focus on mitochondrial quality control mechanisms relying on the Ub-mediated protein degradation, such as mitochondria-specific autophagy and the mitochondrial arm of the Ub proteasome system (UPS). We highlight the importance of a widening perspective of how these pathways protect mitochondria from proteotoxic stress to better understand mitochondrial proteotoxicity in overlapping pathophysiological pathways. Implications of these mechanisms in disease development are also briefly summarized.
    Keywords:  Mitochondria; Mitophagy; Proteotoxicity; Quality control; Ubiquitin
    DOI:  https://doi.org/10.1007/s00018-022-04604-8
  6. Neuroscience. 2022 Oct 21. pii: S0306-4522(22)00524-3. [Epub ahead of print]
    Dual role of IRE1α-XBP1 signaling in neurodegenerative diseases.
    Cailin Wang, Yanmin Chang, Jiahui Zhu, Rong Ma, Gang Li.
      The prevalence of neurodegenerative disease has increased as an outcome of the aging population, and effective clinical treatments for such diseases are lacking. Endoplasmic reticulum dysfunction has been identified as a causative factor in various neurological disorders. The inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) signaling pathway is the most conserved branch of the unfolded protein response, functioning in both physiological and pathological processes. The modulation of IRE1α-XBP1 signaling via genetic manipulation or drug administration has opposite effects in multiple disease models of neurodegeneration, indicating the complex and heterogeneous role of IRE1α-XBP1 signaling among neurodegenerative diseases and even at different stages within the same disease. Herein, we focus on the multifaceted nature of IRE1α-XBP1 signaling and provide a detailed overview of the latest findings regarding its biological relevance in brain physiology and neurodegenerative disease pathobiology. Moreover, the possible pharmacological targets in the IRE1α-XBP1 axis are discussed.
    Keywords:  IRE1α; XBP1; autophagy; calcium; neurodegeneration; neuroinflammation; unfolded protein response
    DOI:  https://doi.org/10.1016/j.neuroscience.2022.10.014
  7. Curr Issues Mol Biol. 2022 Oct 10. 44(10): 4748-4768
    Heat-Induced Proteotoxic Stress Response in Placenta-Derived Stem Cells (PDSCs) Is Mediated through HSPA1A and HSPA1B with a Potential Higher Role for HSPA1B.
    Bothina Mohammed Alharbi, Aisha Bugshan, Azhaar Almozel, Reem Alenzi, Abderrezak Bouchama, Tanvir Khatlani, Sameer Mohammad, Shuja Shafi Malik.
      Placenta-derived stem cells (PDSCs), due to unique traits such as mesenchymal and embryonic characteristics and the absence of ethical constraints, are in a clinically and therapeutically advantageous position. To aid in stemness maintenance, counter pathophysiological stresses, and withstand post-differentiation challenges, stem cells require elevated protein synthesis and consequently augmented proteostasis. Stem cells exhibit source-specific proteostasis traits, making it imperative to study them individually from different sources. These studies have implications for understanding stem cell biology and exploitation in the augmentation of therapeutic applications. Here, we aim to identify the primary determinants of proteotoxic stress response in PDSCs. We generated heat-induced dose-responsive proteotoxic stress models of three stem cell types: placental origin cells, the placenta-derived mesenchymal stem cells (pMSCs), maternal origin cells, the decidua parietalis mesenchymal stem cells (DPMSCs), and the maternal-fetal interface cells, decidua basalis mesenchymal stem cells (DBMSCs), and measured stress induction through biochemical and cell proliferation assays. RT-PCR array analysis of 84 genes involved in protein folding and protein quality control led to the identification of Hsp70 members HSPA1A and HSPA1B as the prominent ones among 17 significantly expressed genes and with further analysis at the protein level through Western blotting. A kinetic analysis of HSPA1A and HSPA1B gene and protein expression allowed a time series evaluation of stress response. As identified by protein expression, an active stress response is in play even at 24 h. More prominent differences in expression between the two homologs are detected at the translational level, alluding to a potential higher requirement for HSPA1B during proteotoxic stress response in PDSCs.
    Keywords:  HSPA1A; HSPA1B; chaperones; heat shock; placenta; placenta-derived stem cells; proteostasis; stem cells; stress response
    DOI:  https://doi.org/10.3390/cimb44100324
  8. Trends Immunol. 2022 Oct 25. pii: S1471-4906(22)00229-0. [Epub ahead of print]
    Calreticulin surface presentation can promote quality control of hematopoietic stem cells.
    Lorenzo Galluzzi, Guido Kroemer.
      Endoplasmic reticulum stress can stimulate calreticulin (CALR) presentation on the cell surface, promoting the phagocytic uptake of stressed cells by myeloid cells. Recent findings from Wattrus et al. demonstrate that zebrafish and mouse embryonic macrophages engulf CALR-exposing nascent hematopoietic stem cells to ensure the selective survival of stem cells apt for adult hematopoiesis.
    Keywords:  autophagy; cancer immunosurveillance; hematopoiesis; immunogenic cell death; sterile inflammation
    DOI:  https://doi.org/10.1016/j.it.2022.10.008
  9. Nat Commun. 2022 Oct 25. 13(1): 6331
    Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention.
    Laura Matabishi-Bibi, Drice Challal, Mara Barucco, Domenico Libri, Anna Babour.
      Cellular homeostasis is maintained by surveillance mechanisms that intervene at virtually every step of gene expression. In the nucleus, the yeast chromatin remodeler Isw1 holds back maturing mRNA ribonucleoparticles to prevent their untimely export, but whether this activity operates beyond quality control of mRNA biogenesis to regulate gene expression is unknown. Here, we identify the mRNA encoding the central effector of the unfolded protein response (UPR) HAC1, as an Isw1 RNA target. The direct binding of Isw1 to the 3' untranslated region of HAC1 mRNA restricts its nuclear export and is required for accurate UPR abatement. Accordingly, ISW1 inactivation sensitizes cells to endoplasmic reticulum (ER) stress while its overexpression reduces UPR induction. Our results reveal an unsuspected mechanism, in which binding of ER-stress induced Isw1 to HAC1 mRNA limits its nuclear export, providing a feedback loop that fine-tunes UPR attenuation to guarantee homeostatic adaptation to ER stress.
    DOI:  https://doi.org/10.1038/s41467-022-34133-8
  10. Nat Neurosci. 2022 Oct 27.
    CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states.
    Kun Leng, Indigo V L Rose, Hyosung Kim, Wenlong Xia, Wilber Romero-Fernandez, Brendan Rooney, Mark Koontz, Emmy Li, Yan Ao, Shinong Wang, Mitchell Krawczyk, Julia Tcw, Alison Goate, Ye Zhang, Erik M Ullian, Michael V Sofroniew, Stephen P J Fancy, Matthew S Schrag, Ethan S Lippmann, Martin Kampmann.
      Astrocytes become reactive in response to insults to the central nervous system by adopting context-specific cellular signatures and outputs, but a systematic understanding of the underlying molecular mechanisms is lacking. In this study, we developed CRISPR interference screening in human induced pluripotent stem cell-derived astrocytes coupled to single-cell transcriptomics to systematically interrogate cytokine-induced inflammatory astrocyte reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures, one promoted by STAT3 and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in human brains in Alzheimer's disease and hypoxic-ischemic encephalopathy. Furthermore, we validated that markers of these signatures were regulated by STAT3 in vivo using a mouse model of neuroinflammation. These results and the platform that we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.
    DOI:  https://doi.org/10.1038/s41593-022-01180-9
  11. Protein Sci. 2022 Nov;31(11): e4448
    Chaperoning activity of the cyclophilin family prevents tau aggregation.
    Shannon E Hill, Abigail R Esquivel, Santiago Rodriguez Ospina, Lauren M Rahal, Chad A Dickey, Laura J Blair.
      Tauopathies, such as Alzheimer's disease, are characterized by the misfolding and progressive accumulation of the microtubule associated protein tau. Chaperones, tasked with maintaining protein homeostasis, can become imbalanced with age and contribute to the progression of neurodegenerative disease. Cyclophilins are a promising pool of underinvestigated chaperones with peptidyl-prolyl isomerase activity that may play protective roles in regulating tau aggregation. Using a Thioflavin T fluorescence-based assay to monitor in vitro tau aggregation, all eight cyclophilins, which include PPIA to PPIH prevent tau aggregation, with PPIB, PPIC, PPID, and PPIH showing the greatest inhibition. The low thermal stability of PPID and the strong heparin binding of PPIB undermines the simplistic interpretation of reduced tau aggregation. In a cellular model of tau accumulation, all cyclophilins, except PPID and PPIH, reduce insoluble tau. PPIB, PPIC, PPIE, and PPIF also reduce soluble tau levels with PPIC exclusively protecting cells from tau seeding. Overall, this study demonstrates cyclophilins prevent tau fibril formation and many reduce cellular insoluble tau accumulation with PPIC having the greatest potential as a molecular tool to mitigate tau seeding and accumulation.
    Keywords:  FRET biosensor cell; PPIase; Thioflavin T; cyclophilin; heparin binding; molecular chaperone; peptidyl-prolyl isomerase; tau; tau seeding; thermal stability
    DOI:  https://doi.org/10.1002/pro.4448
  12. Nat Rev Mol Cell Biol. 2022 Oct 27.
    The mechanisms and roles of selective autophagy in mammals.
    Jose Norberto S Vargas, Maho Hamasaki, Tsuyoshi Kawabata, Richard J Youle, Tamotsu Yoshimori.
      Autophagy is a process that targets various intracellular elements for degradation. Autophagy can be non-selective - associated with the indiscriminate engulfment of cytosolic components - occurring in response to nutrient starvation and is commonly referred to as bulk autophagy. By contrast, selective autophagy degrades specific targets, such as damaged organelles (mitophagy, lysophagy, ER-phagy, ribophagy), aggregated proteins (aggrephagy) or invading bacteria (xenophagy), thereby being importantly involved in cellular quality control. Hence, not surprisingly, aberrant selective autophagy has been associated with various human pathologies, prominently including neurodegeneration and infection. In recent years, considerable progress has been made in understanding mechanisms governing selective cargo engulfment in mammals, including the identification of ubiquitin-dependent selective autophagy receptors such as p62, NBR1, OPTN and NDP52, which can bind cargo and ubiquitin simultaneously to initiate pathways leading to autophagy initiation and membrane recruitment. This progress opens the prospects for enhancing selective autophagy pathways to boost cellular quality control capabilities and alleviate pathology.
    DOI:  https://doi.org/10.1038/s41580-022-00542-2
  13. Science. 2022 Oct 28. 378(6618): 345-346
    A big step toward mirror-image ribosomes.
    Robert F Service.
      Synthetic protein factories could one day make durable drugs the body can't break down.
    DOI:  https://doi.org/10.1126/science.adf4963
  14. Front Mol Neurosci. 2022 ;15 1049914
    Editorial: Apoptosis, autophagy, and mitophagy dysfunction in Alzheimer's disease: Evolving emergence and mechanisms.
    Rajkumar Singh Kalra, Ramesh Kandimalla, Binukumar Bk.
      
    Keywords:  Alzheimer's disease; amyloid-β plaques; apoptosis; autophagy; mitophagy; neuro-fibrillary tangles; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3389/fnmol.2022.1049914
  15. Biomedicines. 2022 Oct 08. pii: 2515. [Epub ahead of print]10(10):
    Therapeutic Antiaging Strategies.
    Shailendra Kumar Mishra, Vyshnavy Balendra, Josephine Esposto, Ahmad A Obaid, Ricardo B Maccioni, Niraj Kumar Jha, George Perry, Mahmoud Moustafa, Mohammed Al-Shehri, Mahendra P Singh, Anmar Anwar Khan, Emanuel Vamanu, Sandeep Kumar Singh.
      Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.
    Keywords:  aging; antiaging strategies; hallmarks; risk factors; therapeutic agent
    DOI:  https://doi.org/10.3390/biomedicines10102515
  16. Aging (Albany NY). 2022 Oct 25. 14(undefined):
    Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan.
    Prameet Kaur, Agimaa Otgonbaatar, Anupriya Ramamoorthy, Ellora Hui Zhen Chua, Nathan Harmston, Jan Gruber, Nicholas S Tolwinski.
      Why biological age is a major risk factor for many of the most important human diseases remains mysterious. We know that as organisms age, stem cell pools are exhausted while senescent cells progressively accumulate. Independently, induction of pluripotency via expression of Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) and clearance of senescent cells have each been shown to ameliorate cellular and physiological aspects of aging, suggesting that both processes are drivers of organismal aging. But stem cell exhaustion and cellular senescence likely interact in the etiology and progression of age-dependent diseases because both undermine tissue and organ homeostasis in different if not complementary ways. Here, we combine transient cellular reprogramming (stem cell rejuvenation) with targeted removal of senescent cells to test the hypothesis that simultaneously targeting both cell-fate based aging mechanisms will maximize life and health span benefits. We find that OKSM extends lifespan and show that both interventions protect the intestinal stem cell pool, lower inflammation, activate pro-stem cell signaling pathways, and synergistically improve health and lifespan. Our findings suggest that a combination therapy, simultaneously replacing lost stem cells and removing senescent cells, shows synergistic potential for anti-aging treatments. Our finding that transient expression of both is the most effective suggests that drug-based treatments in non-genetically tractable organisms will likely be the most translatable.
    Keywords:  aging; senescence; stem cells
    DOI:  https://doi.org/10.18632/aging.204347
  17. Cells. 2022 Oct 17. pii: 3258. [Epub ahead of print]11(20):
    An Alzheimer's Disease Patient-Derived Olfactory Stem Cell Model Identifies Gene Expression Changes Associated with Cognition.
    Laura M Rantanen, Maina Bitar, Riikka Lampinen, Romal Stewart, Hazel Quek, Lotta E Oikari, Carla Cunί-Lόpez, Ratneswary Sutharsan, Gayathri Thillaiyampalam, Jamila Iqbal, Daniel Russell, Elina Penttilä, Heikki Löppönen, Juha-Matti Lehtola, Toni Saari, Sanna Hannonen, Anne M Koivisto, Larisa M Haupt, Alan Mackay-Sim, Alexandre S Cristino, Katja M Kanninen, Anthony R White.
      An early symptom of Alzheimer's disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.
    Keywords:  AKAP6; Alzheimer’s disease; RNA Sequencing; aging; cognition; mild cognitive impairment; olfactory neurosphere-derived cells; patient-derived olfactory mucosa
    DOI:  https://doi.org/10.3390/cells11203258
  18. Mol Cell. 2022 Oct 15. pii: S1097-2765(22)00956-X. [Epub ahead of print]
    ATP13A1 prevents ERAD of folding-competent mislocalized and misoriented proteins.
    Michael J McKenna, Benjamin M Adams, Vincent Chu, Joao A Paulo, Sichen Shao.
      The biosynthesis of thousands of proteins requires targeting a signal sequence or transmembrane segment (TM) to the endoplasmic reticulum (ER). These hydrophobic ɑ helices must localize to the appropriate cellular membrane and integrate in the correct topology to maintain a high-fidelity proteome. Here, we show that the P5A-ATPase ATP13A1 prevents the accumulation of mislocalized and misoriented proteins, which are eliminated by different ER-associated degradation (ERAD) pathways in mammalian cells. Without ATP13A1, mitochondrial tail-anchored proteins mislocalize to the ER through the ER membrane protein complex and are cleaved by signal peptide peptidase for ERAD. ATP13A1 also facilitates the topogenesis of a subset of proteins with an N-terminal TM or signal sequence that should insert into the ER membrane with a cytosolic N terminus. Without ATP13A1, such proteins accumulate in the wrong orientation and are targeted for ERAD by distinct ubiquitin ligases. Thus, ATP13A1 prevents ERAD of diverse proteins capable of proper folding.
    Keywords:  ER-associated degradation; protein localization; protein topology; quality control; signal sequence; transmembrane proteins
    DOI:  https://doi.org/10.1016/j.molcel.2022.09.035
  19. J Immunol. 2022 Oct 26. pii: ji2200518. [Epub ahead of print]
    ER-phagy Is Involved in the Degradation of Collagen I by IL-1β in Human Amnion in Parturition.
    Ya-Bing Mi, Xiao-Hua Liu, Wang-Sheng Wang, Lu-Yao Wang, Li-Jun Ling, Kang Sun, Hao Ying.
      The process of parturition is associated with inflammation within the uterine tissues, and IL-1β is a key proinflammatory cytokine involved. Autophagy is emerging as an important pathway to remove redundant cellular components. However, it is not known whether IL-1β employs the autophagy pathway to degrade collagen, thereby participating in membrane rupture at parturition. In this study, we investigated this issue in human amnion. Results showed that IL-1β levels were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture, which was accompanied by decreased abundance of COL1A1 and COL1A2 protein but not their mRNA, the two components of collagen I. Consistently, IL-1β treatment of cultured primary human amnion fibroblasts reduced COL1A1 and COL1A2 protein but not their mRNA abundance along with increased abundance of autophagy activation markers, including the microtubule-associated protein L chain 3β II/I ratio and autophagy-related 7 (ATG7) in the cells. The reduction in COL1A1 and COL1A2 protein abundance induced by IL-1β could be blocked by the lysosome inhibitor chloroquine or small interfering RNA-mediated knockdown of ATG7 or ER-phagy receptor FAM134C, suggesting that FAM134C-mediated ER-phagy was involved in IL-1β-induced reduction in COL1A1 and COL1A2 protein in amnion fibroblasts. Consistently, levels of L chain 3β II/I ratio, ATG7, and FAM134C were significantly increased in human amnion obtained from deliveries with spontaneous labor and membrane rupture. Conclusively, increased IL-1β abundance in human amnion may stimulate ER-phagy-mediated COL1A1 and COL1A2 protein degradation in amnion fibroblasts, thereby participating in membrane rupture at parturition.
    DOI:  https://doi.org/10.4049/jimmunol.2200518
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