bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2021–10–03
27 papers selected by
Rich Giadone, Harvard University
  1. The heat shock response and small molecule regulators.
  2. Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.
  3. Autophagy and the Hallmarks of Aging.
  4. Surf4 facilitates reprogramming by activating the cellular response to endoplasmic reticulum stress.
  5. Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans.
  6. Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion.
  7. Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology.
  8. ER stress promotes HBV production by enhancing utilization of the autophagosome- multivesicular body axis.
  9. Tauroursodeoxycholic Acid Attenuates Diet-Induced and Age-Related Peripheral Endoplasmic Reticulum Stress and Cerebral Amyloid Pathology in a Mouse Model of Alzheimer's Disease.
  10. MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma.
  11. Stem cells.
  12. Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques.
  13. Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies.
  14. Alzheimer's Disease: A Molecular View of β-Amyloid Induced Morbific Events.
  15. Advances in ER-Phagy and Its Diseases Relevance.
  16. TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.
  17. Effects of Aβ-derived peptide fragments on fibrillogenesis of Aβ.
  18. Therapeutic Potential of Human Stem Cell Implantation in Alzheimer's Disease.
  19. Female Mice Reaching Exceptionally High Old Age Have Preserved 20S Proteasome Activities.
  20. Label-Free Infrared Spectroscopic Imaging Reveals Heterogeneity of β-Sheet Aggregates in Alzheimer's Disease.
  21. Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses.
  22. Single-cell nuclear architecture across cell types in the mouse brain.
  23. Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson's Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology.
  24. Human cardiac stem cells rejuvenated by modulating autophagy with MHY-1685 enhance the therapeutic potential for cardiac repair.
  25. The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes.
  26. Oxidative Stress and Beta Amyloid in Alzheimer's Disease. Which Comes First: The Chicken or the Egg?
  27. Probabilistic Critical Controllability Analysis of Protein Interaction Networks Integrating Normal Brain Ageing Gene Expression Profiles.
  1. Eur J Med Chem. 2021 Sep 13. pii: S0223-5234(21)00695-4. [Epub ahead of print]226 113846
    The heat shock response and small molecule regulators.
    Margaret K Kurop, Cormac M Huyen, John H Kelly, Brian S J Blagg.
      The heat shock response (HSR) is a highly conserved cellular pathway that is responsible for stress relief and the refolding of denatured proteins [1]. When a host cell is exposed to conditions such as heat shock, ischemia, or toxic substances, heat shock factor-1 (HSF-1), a transcription factor, activates the genes that encode for the heat shock proteins (Hsps), which are a family of proteins that work alongside other chaperones to relieve stress and refold proteins that have been denatured (Burdon, 1986) [2]. Along with the refolding of denatured proteins, Hsps facilitate the removal of misfolded proteins by escorting them to degradation pathways, thereby preventing the accumulation of misfolded proteins [3]. Research has indicated that many pathological conditions, such as diabetes, cancer, neuropathy, cardiovascular disease, and aging have a negative impact on HSR function and are commonly associated with misfolded protein aggregation [4,5]. Studies indicate an interplay between mitochondrial homeostasis and HSF-1 levels can impact stress resistance, proteostasis, and malignant cell growth, which further support the role of Hsps in pathological and metabolic functions [6]. On the other hand, Hsp activation by specific small molecules can induce the heat shock response, which can afford neuroprotection and other benefits [7]. This review will focus on the modulation of Hsps and the HSR as therapeutic options to treat these conditions.
    Keywords:  Cancer; HSF1; Heat shock response; Hsp90; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.ejmech.2021.113846
  2. Cells. 2021 Sep 17. pii: 2454. [Epub ahead of print]10(9):
    Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress.
    Yun Yeong Lee, Eun Sol Gil, In Hye Jeong, Hantai Kim, Jeong Hun Jang, Yun-Hoon Choung.
      Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.
    Keywords:  age-related hearing loss; apoptosis; endoplasmic reticulum stress; heat shock factor 1; heat shock protein
    DOI:  https://doi.org/10.3390/cells10092454
  3. Ageing Res Rev. 2021 Sep 23. pii: S1568-1637(21)00215-4. [Epub ahead of print] 101468
    Autophagy and the Hallmarks of Aging.
    Susmita Kaushik, Inmaculada Tasset, Esperanza Arias, Olatz Pampliega, Esther Wong, Marta Martinez-Vicente, Ana Maria Cuervo.
      Autophagy, an essential cellular process that mediates degradation of proteins and organelles in lysosomes, has been tightly linked to cellular quality control for its role as part of the proteostasis network. The current interest in identifying the cellular and molecular determinants of aging, has highlighted the important contribution of malfunctioning of autophagy with age to the loss of proteostasis that characterizes all old organisms. However, the diversity of cellular functions of the different types of autophagy and the often reciprocal interactions of autophagy with other determinants of aging, is placing autophagy at the center of the aging process. In this work, we summarize evidence for the contribution of autophagy to health- and lifespan and provide examples of the bidirectional interplay between autophagic pathways and several of the so-called hallmarks of aging. This central role of autophagy in aging, and the dependence on autophagy of many geroprotective interventions, has motivated a search for direct modulators of autophagy that could be used to slow aging and extend healthspan. Here, we review some of those ongoing therapeutic efforts and comment on the potential of targeting autophagy in aging.
    Keywords:  aging; chaperones; lysosomes; organelle turnover; proteolysis; proteostasis
    DOI:  https://doi.org/10.1016/j.arr.2021.101468
  4. Cell Prolif. 2021 Sep 28. e13133
    Surf4 facilitates reprogramming by activating the cellular response to endoplasmic reticulum stress.
    Li Wu, Shengxiang He, Wen Ye, Jiacheng Shen, Kun Zhao, Yanping Zhang, Ran Zhang, Junhao Wei, Shuyuan Cao, Kang Chen, Rongrong Le, Chenxiang Xi, Xiaochen Kou, Yanhong Zhao, Hong Wang, Lan Kang, Shaorong Gao.
       OBJECTIVES: Maternal factors that are enriched in oocytes have attracted great interest as possible key factors in somatic cell reprogramming. We found that surfeit locus protein 4 (Surf4), a maternal factor, can facilitate the generation of induced pluripotent stem cells (iPSCs) previously, but the mechanism remains elusive.
    MATERIALS AND METHODS: In this study, we investigated the function and mechanism of Surf4 in somatic cell reprogramming using a secondary reprogramming system. Alkaline phosphatase (AP) staining, qPCR and immunofluorescence (IF) staining of expression of related markers were used to evaluate efficiency of iPSCs derived from mouse embryonic fibroblasts. Embryoid body and teratoma formation assays were performed to evaluate the differentiation ability of the iPSC lines. RNA-seq, qPCR and western blot analysis were applied to validate the downstream targets of Surf4.
    RESULTS: Surf4 can significantly facilitate the generation of iPSCs in a proliferation-independent manner. When co-expressed with Oct4, Sox2, Klf4 and c-Myc (OSKM), Surf4 can activate the response to endoplasmic reticulum (ER) stress at the early stage of reprogramming. We further demonstrated that Hspa5, a major ER chaperone, and the active spliced form of Xbp1 (sXbp1), a major mediator of ER stress, can mimic the effects of Surf4 on somatic cell reprogramming. Concordantly, blocking the unfolded protein response compromises the effect of Surf4 on reprogramming.
    CONCLUSIONS: Surf4 promotes somatic cell reprogramming by activating the response to ER stress.
    DOI:  https://doi.org/10.1111/cpr.13133
  5. J Vis Exp. 2021 Sep 07.
    Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans.
    Maria I Lazaro-Pena, Adam B Cornwell, Andrew V Samuelson.
      The ability to maintain proper function and folding of the proteome (protein homeostasis) declines during normal aging, facilitating the onset of a growing number of age-associated diseases. For instance, proteins with polyglutamine expansions are prone to aggregation, as exemplified with the huntingtin protein and concomitant onset of Huntington's disease. The age-associated deterioration of the proteome has been widely studied through the use of transgenic Caenorhabditis elegans expressing polyQ repeats fused to a yellow fluorescent protein (YFP). This polyQ::YFP transgenic animal model facilitates the direct quantification of the age-associated decline of the proteome through imaging the progressive formation of fluorescent foci (i.e., protein aggregates) and subsequent onset of locomotion defects that develop as a result of the collapse of the proteome. Further, the expression of the polyQ::YFP transgene can be driven by tissue-specific promoters, allowing the assessment of proteostasis across tissues in the context of an intact multicellular organism. This model is highly amenable to genetic analysis, thus providing an approach to quantify aging that is complementary to lifespan assays. We describe how to accurately measure polyQ::YFP foci formation within either neurons or body wall muscle during aging, and the subsequent onset of behavioral defects. Next, we highlight how these approaches can be adapted for higher throughput, and potential future applications using other emerging strategies for C. elegans genetic analysis.
    DOI:  https://doi.org/10.3791/61100
  6. Biomedicines. 2021 Sep 07. pii: 1178. [Epub ahead of print]9(9):
    Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion.
    Mikhail Menshikov, Ekaterina Zubkova, Iuri Stafeev, Yelena Parfyonova.
      Mesenchymal stem cells (MSC) are multipotent cells capable to differentiate into adipogenic, osteogenic, and chondrogenic directions, possessing immunomodulatory activity and a capability to stimulate angiogenesis. A scope of these features and capabilities makes MSC a significant factor of tissue homeostasis and repair. Among factors determining the fate of MSC, a prominent place belongs to autophagy, which is activated under different conditions including cell starvation, inflammation, oxidative stress, and some others. In addition to supporting cell homeostasis by elimination of protein aggregates, and non-functional and damaged proteins, autophagy is a necessary factor of change in cell phenotype on the process of cell differentiation. In present review, some mechanisms providing participation of autophagy in cell differentiation are discussed.
    Keywords:  autophagy; differentiation; immunomodulation; mesenchymal stem cells; signal transduction
    DOI:  https://doi.org/10.3390/biomedicines9091178
  7. Metabolites. 2021 Sep 15. pii: 622. [Epub ahead of print]11(9):
    Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology.
    Xiaoguang Liu, Kaluvu Balaraman, Ciarán C Lynch, Michaeline Hebron, Christian Wolf, Charbel Moussa.
      Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.
    Keywords:  USP13 inhibitors; Ubiquitin Specific Protease-13 (USP13); neurodegeneration
    DOI:  https://doi.org/10.3390/metabo11090622
  8. Hepatology. 2021 Sep 28.
    ER stress promotes HBV production by enhancing utilization of the autophagosome- multivesicular body axis.
    Xueyu Wang, Zhiqiang Wei, Bin Cheng, Jia Li, Yulin He, Tingyu Lan, Thekla Kemper, Yong Lin, Bin Jiang, Yongfang Jiang, Zhongji Meng, Mengji Lu.
       BACKGROUND & AIMS: Hepatitis B virus (HBV) infection has been reported to trigger endoplasmic reticulum (ER) stress and initiate autophagy. However, how ER stress and autophagy influence HBV production remains elusive. Here, we studied the effect of tunicamycin (TM), an N-glycosylation inhibitor and ER stress inducer, on HBV replication and secretion, and examined the underlying mechanisms.
    APPROACH & RESULTS: PDI (an ER marker), LC3 (an autophagosome marker) and p62 (a typical cargo for autophagic degradation) expression were tested in the liver tissues of patients with chronic HBV infection and hepatoma cell lines. The role of TM treatment in HBV production and trafficking was examined in hepatoma cell lines. TM treatment that mimics HBV infection triggered ER stress and increased autophagosome formation, resulting in enhanced HBV replication and the secretion of subviral particles (SVPs) and naked capsids. Additionally, TM reduced the number of early endosomes and HBV surface antigen (HBsAg) localization in this compartment, causing HBsAg/SVPs accumulate in the ER. Thus, TM-induced autophagosome formation serves as an alternative pathway for HBsAg/SVPs trafficking. Importantly, TM inhibited autophagosome-lysosome fusion, accompanied by enhanced autophagosome-late endosome/multivesicular body (MVB) fusion to release HBsAg/SVPs through or along with exosome release. Notably, TM treatment inhibited the HBsAg glycosylation, resulting in impairment of the HBV virions envelopment and secretion, but it was not critical for HBsAg/SVPs trafficking in our cell systems.
    CONCLUSIONS: TM-induced ER stress and autophagic flux promoted HBV replication and the release of SVPs and naked capsids through the autophagosome-late endosome/MVB axis.
    Keywords:  Hepatitis B virus; autophagosome; multivesicular bodies/MVBs; vesicular trafficking
    DOI:  https://doi.org/10.1002/hep.32178
  9. J Prev Alzheimers Dis. 2021 ;8(4): 483-494
    Tauroursodeoxycholic Acid Attenuates Diet-Induced and Age-Related Peripheral Endoplasmic Reticulum Stress and Cerebral Amyloid Pathology in a Mouse Model of Alzheimer's Disease.
    T Ochiai, T Nagayama, K Matsui, K Amano, T Sano, T Wakabayashi, T Iwatsubo.
       BACKGROUND: Obesity and diabetes are well-established risk factors of Alzheimer's disease (AD). In the brains of patients with AD and model mice, diabetes-related factors have been implicated in the pathological changes of AD. However, the molecular mechanistic link between the peripheral metabolic state and AD pathophysiology have remained elusive. Endoplasmic reticulum (ER) stress is known as one of the major contributors to the metabolic abnormalities in obesity and diabetes. Interventions aimed at reducing ER stress have been shown to improve the systemic metabolic abnormalities, although their effects on the AD pathology have not been extensively studied.
    OBJECTIVES: We examined whether interventions targeting ER stress attenuate the obesity/diabetes-induced Aβ accumulation in brains. We also aimed to determine whether ER stress that took place in the peripheral tissues or central nervous system was more important in the Aβ neuropathology. Furthermore, we explored if age-related metabolic abnormalities and Aβ accumulation could be suppressed by reducing ER stress.
    METHODS: APP transgenic mice (A7-Tg), which exhibit Aβ accumulation in the brain, were used as a model of AD to analyze parameters of peripheral metabolic state, ER stress, and Aβ pathology in the brain. Intraperitoneal or intracerebroventricular administration of taurodeoxycholic acid (TUDCA), a chemical chaperone, was performed in high-fat diet (HFD)-fed A7-Tg mice for ~1 month, followed by analyses at 9 months of age. Mice fed a normal diet were treated with TUDCA by drinking water for 4 months and intraperitoneally for 1 month in parallel, and analyzed at 15 months of age.
    RESULTS: Intraperitoneal administration of TUDCA suppressed ER stress in the peripheral tissues and ameliorated the HFD-induced obesity and insulin resistance. Concomitantly, Aβ levels in the brain were significantly reduced. In contrast, intracerebroventricular administration of TUDCA had no effect on the Aβ levels. Peripheral administration of TUDCA was also effective against the age-related obesity and insulin resistance, and markedly reduced amyloid accumulation.
    CONCLUSIONS: Interventions that target peripheral ER stress might be beneficial therapeutic and prevention strategies against brain Aβ pathology associated with metabolic overload and aging.
    Keywords:  Alzheimer’s disease; Aβ; ER stress; diabetes; obesity
    DOI:  https://doi.org/10.14283/jpad.2021.33
  10. J Invest Dermatol. 2021 Sep 23. pii: S0022-202X(21)01224-0. [Epub ahead of print]
    MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma.
    Charles H Adelmann, Inbal Rachmin, David E Fisher.
      In a new article in the Journal of Investigative Dermatology, Wang et al. (2021) report that mitochondrial quality control modulates responses to endoplasmic reticulum (ER) stress in melanoma. They implicate a linear pathway of XBP1, MARCH5, and MFN2 that act together to regulate mitochondrial fission and mitophagy and ultimately mediate melanoma cell sensitivity to ER stress. This work informs therapeutic combinations and biomarker strategies for targeting melanoma organellar homeostasis as well as for life‒death decisions.
    DOI:  https://doi.org/10.1016/j.jid.2021.05.003
  11. Nature. 2021 Sep;597(7878): S5
    Stem cells.
    Richard Hodson.
      
    Keywords:  Biotechnology; Medical research; Regeneration; Stem cells
    DOI:  https://doi.org/10.1038/d41586-021-02620-5
  12. Mol Neurodegener. 2021 Sep 25. 16(1): 68
    Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques.
    Pranav Preman, Julia Tcw, Sara Calafate, An Snellinx, Maria Alfonso-Triguero, Nikky Corthout, Sebastian Munck, Dietmar Rudolf Thal, Alison M Goate, Bart De Strooper, Amaia M Arranz.
       BACKGROUND: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.
    RESULTS: To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background.
    CONCLUSIONS: In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.
    Keywords:  Alzheimer’s disease; Amyloid plaques; Apolipoprotein E (APOE); Astrocytes; Chimeric mouse models; Human induced pluripotent stem cells (hiPSCs)
    DOI:  https://doi.org/10.1186/s13024-021-00487-8
  13. Metabolites. 2021 Aug 31. pii: 588. [Epub ahead of print]11(9):
    Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies.
    Margarita-Elena Papandreou, Nektarios Tavernarakis.
      Progressive accumulation of damaged cellular constituents contributes to age-related diseases. Autophagy is the main catabolic process, which recycles cellular material in a multitude of tissues and organs. Autophagy is activated upon nutrient deprivation, and oncogenic, heat or oxidative stress-induced stimuli to selectively degrade cell constituents and compartments. Specificity and accuracy of the autophagic process is maintained via the precision of interaction of autophagy receptors or adaptors and substrates by the intricate, stepwise orchestration of specialized integrating stimuli. Polymorphisms in genes regulating selective autophagy have been linked to aging and age-associated disorders. The involvement of autophagy perturbations in aging and disease indicates that pharmacological agents balancing autophagic flux may be beneficial, in these contexts. Here, we introduce the modes and mechanisms of selective autophagy, and survey recent experimental evidence of dysfunctional autophagy triggering severe pathology. We further highlight identified pharmacological targets that hold potential for developing therapeutic interventions to alleviate cellular autophagic cargo burden and associated pathologies.
    Keywords:  age-related disease; aggrephagy; aging; mitophagy; neurodegeneration; nucleophagy; pexophagy; rapamycin; selective autophagy
    DOI:  https://doi.org/10.3390/metabo11090588
  14. Biomedicines. 2021 Sep 01. pii: 1126. [Epub ahead of print]9(9):
    Alzheimer's Disease: A Molecular View of β-Amyloid Induced Morbific Events.
    Rajmohamed Mohamed Asik, Natarajan Suganthy, Mohamed Asik Aarifa, Arvind Kumar, Krisztián Szigeti, Domokos Mathe, Balázs Gulyás, Govindaraju Archunan, Parasuraman Padmanabhan.
      Amyloid-β (Aβ) is a dynamic peptide of Alzheimer's disease (AD) which accelerates the disease progression. At the cell membrane and cell compartments, the amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretases and engenders the Aβ. In addition, externally produced Aβ gets inside the cells by receptors mediated internalization. An elevated amount of Aβ yields spontaneous aggregation which causes organelles impairment. Aβ stimulates the hyperphosphorylation of tau protein via acceleration by several kinases. Aβ travels to the mitochondria and interacts with its functional complexes, which impairs the mitochondrial function leading to the activation of apoptotic signaling cascade. Aβ disrupts the Ca2+ and protein homeostasis of the endoplasmic reticulum (ER) and Golgi complex (GC) that promotes the organelle stress and inhibits its stress recovery machinery such as unfolded protein response (UPR) and ER-associated degradation (ERAD). At lysosome, Aβ precedes autophagy dysfunction upon interacting with autophagy molecules. Interestingly, Aβ act as a transcription regulator as well as inhibits telomerase activity. Both Aβ and p-tau interaction with neuronal and glial receptors elevate the inflammatory molecules and persuade inflammation. Here, we have expounded the Aβ mediated events in the cells and its cosmopolitan role on neurodegeneration, and the current clinical status of anti-amyloid therapy.
    Keywords:  Alzheimer’s disease; amyloid beta; gene regulation; inflammation; organelle dysfunction
    DOI:  https://doi.org/10.3390/biomedicines9091126
  15. Cells. 2021 Sep 06. pii: 2328. [Epub ahead of print]10(9):
    Advances in ER-Phagy and Its Diseases Relevance.
    Lingang He, Xuehong Qian, Yixian Cui.
      As an important form of selective autophagy in cells, ER-phagy (endoplasmic reticulum-selective autophagy), the autophagic degradation of endoplasmic reticulum (ER), degrades ER membranes and proteins to maintain cellular homeostasis. The relationship between ER-phagy and human diseases, including neurodegenerative disorders, cancer, and other metabolic diseases has been unveiled by extensive research in recent years. Starting with the catabolic process of ER-phagy and key mediators in this pathway, this paper reviews the advances in the mechanism of ER-phagy and its diseases relevance. We hope to provide some enlightenment for further study on ER-phagy and the development of novel therapeutic strategies for related diseases.
    Keywords:  ER-phagy; cancer; metabolic diseases; neurodegenerative diseases; receptor
    DOI:  https://doi.org/10.3390/cells10092328
  16. Redox Biol. 2021 Sep 09. pii: S2213-2317(21)00287-1. [Epub ahead of print]47 102128
    TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.
    Kashi Raj Bhattarai, Hyun-Kyoung Kim, Manoj Chaudhary, Mohammad Mamun Ur Rashid, Jisun Kim, Hyung-Ryong Kim, Han-Jung Chae.
      Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6-/-) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6-/- old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.
    Keywords:  Aging; ER stress response failure; IRE1α modifications; S-nitrosylation; Sulfonation; TMBIM6/BI-1
    DOI:  https://doi.org/10.1016/j.redox.2021.102128
  17. Sci Rep. 2021 Sep 28. 11(1): 19262
    Effects of Aβ-derived peptide fragments on fibrillogenesis of Aβ.
    Faisal Abedin, Nabin Kandel, Suren A Tatulian.
      Amyloid β (Aβ) peptide aggregation plays a central role in Alzheimer's disease (AD) etiology. AD drug candidates have included small molecules or peptides directed towards inhibition of Aβ fibrillogenesis. Although some Aβ-derived peptide fragments suppress Aβ fibril growth, comprehensive analysis of inhibitory potencies of peptide fragments along the whole Aβ sequence has not been reported. The aim of this work is (a) to identify the region(s) of Aβ with highest propensities for aggregation and (b) to use those fragments to inhibit Aβ fibrillogenesis. Structural and aggregation properties of the parent Aβ1-42 peptide and seven overlapping peptide fragments have been studied, i.e. Aβ1-10 (P1), Aβ6-15 (P2), Aβ11-20 (P3), Aβ16-25 (P4), Aβ21-30 (P5), Aβ26-36 (P6), and Aβ31-42 (P7). Structural transitions of the peptides in aqueous buffer have been monitored by circular dichroism and Fourier transform infrared spectroscopy. Aggregation and fibrillogenesis were analyzed by light scattering and thioflavin-T fluorescence. The mode of peptide-peptide interactions was characterized by fluorescence resonance energy transfer. Three peptide fragments, P3, P6, and P7, exhibited exceptionally high propensity for β-sheet formation and aggregation. Remarkably, only P3 and P6 exerted strong inhibitory effect on the aggregation of Aβ1-42, whereas P7 and P2 displayed moderate inhibitory potency. It is proposed that P3 and P6 intercalate between Aβ1-42 molecules and thereby inhibit Aβ1-42 aggregation. These findings may facilitate therapeutic strategies of inhibition of Aβ fibrillogenesis by Aβ-derived peptides.
    DOI:  https://doi.org/10.1038/s41598-021-98644-y
  18. Int J Mol Sci. 2021 Sep 21. pii: 10151. [Epub ahead of print]22(18):
    Therapeutic Potential of Human Stem Cell Implantation in Alzheimer's Disease.
    Hau Jun Chan, Yanshree, Jaydeep Roy, George Lim Tipoe, Man-Lung Fung, Lee Wei Lim.
      Alzheimer's disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.
    Keywords:  Alzheimer’s disease; Induced pluripotent stem cells; embryonic stem cells; mesenchymal stem cells; neural stem cells; neurodegenerative disease; neurogenesis; stem cell therapy; stem cell transplantation; stem cells
    DOI:  https://doi.org/10.3390/ijms221810151
  19. Antioxidants (Basel). 2021 Aug 31. pii: 1397. [Epub ahead of print]10(9):
    Female Mice Reaching Exceptionally High Old Age Have Preserved 20S Proteasome Activities.
    Irene Martínez de Toda, Suresh I S Rattan, Mónica De la Fuente, Lorena Arranz.
      Oxidized, damaged and misfolded proteins accumulate during aging and contribute to impaired cell function and tissue homeodynamics. Damaged proteins are degraded by cellular clearance mechanisms like the 20S proteasome. Aging relates to low 20S proteasome function, whereas long-lived species show high levels. However, contradictory results exist depending on the tissue or cell type and it is unknown how the 20S proteasome functions in exceptionally old mice. The aim of this study was to investigate two proteasome activities (caspase-like and chymotrypsin-like) in several tissues (lung, heart, axillary lymph nodes, liver, kidney) and cells (peritoneal leukocytes) from adult (28 ± 4 weeks, n = 12), old (76 ± 4 weeks, n = 9) and exceptionally old (128 ± 4 weeks, n = 9) BALB/c female mice. The results show different age-related changes depending on the tissue and the activity considered, so there is no universal decline in proteasome function with age in female mice. Interestingly, exceptionally old mice displayed better maintained proteasome activities, suggesting that preserved 20S proteasome is associated with successful aging.
    Keywords:  20S proteasome; aging; caspase-like activity; chymotrypsin-like activity; exceptionally old; healthy aging
    DOI:  https://doi.org/10.3390/antiox10091397
  20. J Phys Chem Lett. 2021 Sep 30. 9662-9671
    Label-Free Infrared Spectroscopic Imaging Reveals Heterogeneity of β-Sheet Aggregates in Alzheimer's Disease.
    Matthew P Confer, Brooke M Holcombe, Abigail G Foes, John M Holmquist, Savannah C Walker, Sanghamitra Deb, Ayanjeet Ghosh.
      The aggregation of the amyloid beta (Aβ) protein into plaques is a pathological feature of Alzheimer's disease (AD). While amyloid aggregates have been extensively studied in vitro, their structural aspects and associated chemistry in the brain are not fully understood. In this report, we demonstrate, using infrared spectroscopic imaging, that Aβ plaques exhibit significant heterogeneities in terms of their secondary structure and phospholipid content. We show that the capabilities of discrete frequency infrared imaging (DFIR) are ideally suited for characterization of amyloid deposits in brain tissues and employ DFIR to identify nonplaque β-sheet aggregates distributed throughout brain tissues. We further demonstrate that phospholipid-rich β-sheet deposits exist outside of plaques in all diseased tissues, indicating their potential clinical significance. This is the very first application of DFIR toward a characterization of protein aggregates in an AD brain and provides a rapid, label-free approach that allows us to uncover β-sheet heterogeneities in the AD, which may be significant for targeted therapeutic strategies in the future.
    DOI:  https://doi.org/10.1021/acs.jpclett.1c02306
  21. Mol Cell Biochem. 2021 Sep 29.
    Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses.
    Sudhir Pandey, Chia-Hua Kuo, William Shao-Tsu Chen, Yu-Lan Yeh, Wei-Wen Kuo, Ray-Jade Chen, Cecilia Hsuan Day, Pei-Ying Pai, Tsung-Jung Ho, Chih-Yang Huang.
      The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIRα in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIRα overexpression enhanced ER stress markers ATF4, ATF6, IRE1α, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIRα concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIRα-induced ER stress responses. Altogether, these findings suggested that IGF-IIRα contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.
    Keywords:  Cardiotoxicity; Doxorubicin; ER stress; H9c2 cells; IGF-IIRα; Transgenic rats
    DOI:  https://doi.org/10.1007/s11010-021-04261-8
  22. Science. 2021 Sep 30. eabj1966
    Single-cell nuclear architecture across cell types in the mouse brain.
    Yodai Takei, Shiwei Zheng, Jina Yun, Sheel Shah, Nico Pierson, Jonathan White, Simone Schindler, Carsten H Tischbirek, Guo-Cheng Yuan, Long Cai.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abj1966
  23. Cells. 2021 Sep 13. pii: 2402. [Epub ahead of print]10(9):
    Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson's Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology.
    Xiaojun Diao, Fei Wang, Andrea Becerra-Calixto, Claudio Soto, Abhisek Mukherjee.
      Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson's disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.
    Keywords:  Lewy bodies; Parkinson’s disease; dopaminergic neurons; iPSC; mitochondria; α-synuclein aggregates
    DOI:  https://doi.org/10.3390/cells10092402
  24. Exp Mol Med. 2021 Sep 28.
    Human cardiac stem cells rejuvenated by modulating autophagy with MHY-1685 enhance the therapeutic potential for cardiac repair.
    Ji Hye Park, Hyeok Kim, Hyung Ryong Moon, Bong-Woo Park, Jae-Hyun Park, Woo-Sup Sim, Jin-Ju Kim, Hye Ji Lim, Yeon-Ju Kim, Seung Taek Ji, Woong Bi Jang, Vinoth Kumar Rethineswaran, Le Thi Hong Van, Ly Thanh Truong Giang, Jisoo Yun, Jong Seong Ha, Kiwon Ban, Hae Young Chung, Sang Hong Baek, Hun-Jun Park, Sang-Mo Kwon.
      Stem cell-based therapies with clinical applications require millions of cells. Therefore, repeated subculture is essential for cellular expansion, which is often complicated by replicative senescence. Cellular senescence contributes to reduced stem cell regenerative potential as it inhibits stem cell proliferation and differentiation as well as the activation of the senescence-associated secretory phenotype (SASP). In this study, we employed MHY-1685, a novel mammalian target of rapamycin (mTOR) inhibitor, and examined its long-term priming effect on the activities of senile human cardiac stem cells (hCSCs) and the functional benefits of primed hCSCs after transplantation. In vitro experiments showed that the MHY-1685‒primed hCSCs exhibited higher viability in response to oxidative stress and an enhanced proliferation potential compared to that of the unprimed senile hCSCs. Interestingly, priming MHY-1685 enhanced the expression of stemness-related markers in senile hCSCs and provided the differentiation potential of hCSCs into vascular lineages. In vivo experiment with echocardiography showed that transplantation of MHY-1685‒primed hCSCs improved cardiac function than that of the unprimed senile hCSCs at 4 weeks post-MI. In addition, hearts transplanted with MHY-1685-primed hCSCs exhibited significantly lower cardiac fibrosis and higher capillary density than that of the unprimed senile hCSCs. In confocal fluorescence imaging, MHY-1685‒primed hCSCs survived for longer durations than that of the unprimed senile hCSCs and had a higher potential to differentiate into endothelial cells (ECs) within the infarcted hearts. These findings suggest that MHY-1685 can rejuvenate senile hCSCs by modulating autophagy and that as a senescence inhibitor, MHY-1685 can provide opportunities to improve hCSC-based myocardial regeneration.
    DOI:  https://doi.org/10.1038/s12276-021-00676-x
  25. Science. 2021 Oct;374(6563): 52-57
    The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes.
    Ngoc-Han Tran, Stephen D Carter, Ann De Mazière, Avi Ashkenazi, Judith Klumperman, Peter Walter, Grant J Jensen.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abh2474
  26. Antioxidants (Basel). 2021 Sep 16. pii: 1479. [Epub ahead of print]10(9):
    Oxidative Stress and Beta Amyloid in Alzheimer's Disease. Which Comes First: The Chicken or the Egg?
    Elena Tamagno, Michela Guglielmotto, Valeria Vasciaveo, Massimo Tabaton.
      The pathogenesis of Alzheimer's disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain's vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer's disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question "which comes first: the chicken or the egg?" remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer's disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.
    Keywords:  Alzheimer’s disease; oxidative stress; β amyloid
    DOI:  https://doi.org/10.3390/antiox10091479
  27. Int J Mol Sci. 2021 Sep 13. pii: 9891. [Epub ahead of print]22(18):
    Probabilistic Critical Controllability Analysis of Protein Interaction Networks Integrating Normal Brain Ageing Gene Expression Profiles.
    Eimi Yamaguchi, Tatsuya Akutsu, Jose C Nacher.
      Recently, network controllability studies have proposed several frameworks for the control of large complex biological networks using a small number of life molecules. However, age-related changes in the brain have not been investigated from a controllability perspective. In this study, we compiled the gene expression profiles of four normal brain regions from individuals aged 20-99 years and generated dynamic probabilistic protein networks across their lifespan. We developed a new algorithm that efficiently identified critical proteins in probabilistic complex networks, in the context of a minimum dominating set controllability model. The results showed that the identified critical proteins were significantly enriched with well-known ageing genes collected from the GenAge database. In particular, the enrichment observed in replicative and premature senescence biological processes with critical proteins for male samples in the hippocampal region led to the identification of possible new ageing gene candidates.
    Keywords:  ageing process; brain; critical controllability; gene expression; probabilistic controllability; protein networks
    DOI:  https://doi.org/10.3390/ijms22189891
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