bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒06‒12
eighteen papers selected by
Rich Giadone
Harvard University
  1. The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.
  2. Multivalent protein-protein interactions are pivotal regulators of eukaryotic Hsp70 complexes.
  3. Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions.
  4. From cradle to grave: neurogenesis, neuroregeneration and neurodegeneration in Alzheimer's and Parkinson's diseases.
  5. Monitoring Protein Import into the Endoplasmic Reticulum in Living Cells with Proximity Labeling.
  6. Protein folding in vitro and in the cell: From a solitary journey to a team effort.
  7. Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
  8. End of the road: from the ER to the proteasome.
  9. The emerging roles of deubiquitinases in plant proteostasis.
  10. Tissue-specific inhibition of protein sumoylation uncovers diverse SUMO functions during C. elegans vulval development.
  11. Autophagy is required for spermatogonial differentiation in the Drosophila testis.
  12. Amyloids on Membrane Interfaces: Implications for Neurodegeneration.
  13. Identifying ribosome heterogeneity using ribosome profiling.
  14. Structures of tau and α-synuclein filaments from brains of patients with neurodegenerative diseases.
  15. Hyperthermia increases HSP production in human PDMCs by stimulating ROS formation, p38 MAPK and Akt signaling, and increasing HSF1 activity.
  16. Arabidopsis HEAT SHOCK FACTOR BINDING PROTEIN is required to limit meiotic crossovers and HEI10 transcription.
  17. Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons.
  18. Generation of an induced pluripotent stem cell line (UCSCi002-A) from a patient with a variant in TARDBP gene associated with familial amyotrophic lateral sclerosis and frontotemporal dementia.
  1. Int J Mol Sci. 2022 May 24. pii: 5894. [Epub ahead of print]23(11):
    The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.
    Soojeong Kim, Doo Kyung Kim, Seho Jeong, Jaemin Lee.
      Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.
    Keywords:  Alzheimer’s disease; ER stress; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; endoplasmic reticulum; misfolded protein; neurodegenerative disease; prion disease; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms23115894
  2. Cell Stress Chaperones. 2022 Jun 07.
    Multivalent protein-protein interactions are pivotal regulators of eukaryotic Hsp70 complexes.
    Oleta T Johnson, Jason E Gestwicki.
      Heat shock protein 70 (Hsp70) is a molecular chaperone and central regulator of protein homeostasis (proteostasis). Paramount to this role is Hsp70's binding to client proteins and co-chaperones to produce distinct complexes, such that understanding the protein-protein interactions (PPIs) of Hsp70 is foundational to describing its function and dysfunction in disease. Mounting evidence suggests that these PPIs include both "canonical" interactions, which are universally conserved, and "non-canonical" (or "secondary") contacts that seem to have emerged in eukaryotes. These two categories of interactions involve discrete binding surfaces, such that some clients and co-chaperones engage Hsp70 with at least two points of contact. While the contributions of canonical interactions to chaperone function are becoming increasingly clear, it can be challenging to deconvolute the roles of secondary interactions. Here, we review what is known about non-canonical contacts and highlight examples where their contributions have been parsed, giving rise to a model in which Hsp70's secondary contacts are not simply sites of additional avidity but are necessary and sufficient to impart unique functions. From this perspective, we propose that further exploration of non-canonical contacts will generate important insights into the evolution of Hsp70 systems and inspire new approaches for developing small molecules that tune Hsp70-mediated proteostasis.
    Keywords:  Bag domain; Hsp110; J-domain protein; Nucleotide exchange factor; Protein aggregation; Protein folding
    DOI:  https://doi.org/10.1007/s12192-022-01281-1
  3. Commun Biol. 2022 Jun 08. 5(1): 557
    Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions.
    Yingjun Liu, Assunta Senatore, Silvia Sorce, Mario Nuvolone, Jingjing Guo, Zeynep H Gümüş, Adriano Aguzzi.
      Mammalian models are essential for brain aging research. However, the long lifespan and poor amenability to genetic and pharmacological perturbations have hindered the use of mammals for dissecting aging-regulatory molecular networks and discovering new anti-aging interventions. To circumvent these limitations, we developed an ex vivo model system that faithfully mimics the aging process of the mammalian brain using cultured mouse brain slices. Genome-wide gene expression analyses showed that cultured brain slices spontaneously upregulated senescence-associated genes over time and reproduced many of the transcriptional characteristics of aged brains. Treatment with rapamycin, a classical anti-aging compound, largely abolished the time-dependent transcriptional changes in naturally aged brain slice cultures. Using this model system, we discovered that prions drastically accelerated the development of age-related molecular signatures and the pace of brain aging. We confirmed this finding in mouse models and human victims of Creutzfeldt-Jakob disease. These data establish an innovative, eminently tractable mammalian model of brain aging, and uncover a surprising acceleration of brain aging in prion diseases.
    DOI:  https://doi.org/10.1038/s42003-022-03496-5
  4. Neural Regen Res. 2022 Dec;17(12): 2606-2614
    From cradle to grave: neurogenesis, neuroregeneration and neurodegeneration in Alzheimer's and Parkinson's diseases.
    Debia Wakhloo, Jane Oberhauser, Angela Madira, Sameehan Mahajani.
      Two of the most common neurodegenerative disorders - Alzheimer's and Parkinson's diseases - are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation. The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer's disease pathology. The major hallmark of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, following the formation of Lewy bodies, which consists primarily of alpha-synuclein aggregates. However, the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood. Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders. Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients. While some publications provide significant findings related to axonal regeneration in Alzheimer's and Parkinson's diseases, they also highlight the limitations and obstacles to the development of neuroregenerative therapies. In this review, we summarize in vitro and in vivo findings related to neurogenesis, neuroregeneration and neurodegeneration in the context of Alzheimer's and Parkinson's diseases.
    Keywords:  Tau; Wallerian degeneration; alpha-synuclein; amyloid beta plaques; autophagy; dopaminergic neurons; human iPSCs; mitochondrial dysfunction; scRNA sequencing; synaptic dysfunction
    DOI:  https://doi.org/10.4103/1673-5374.336138
  5. ACS Chem Biol. 2022 Jun 08.
    Monitoring Protein Import into the Endoplasmic Reticulum in Living Cells with Proximity Labeling.
    Ziqi Lyu, Melody M Sycks, Mateo F Espinoza, Khanh K Nguyen, Maureen R Montoya, Cheska M Galapate, Liangyong Mei, Joseph C Genereux.
      The proper trafficking of eukaryotic proteins is essential to cellular function. Genetic, environmental, and other stresses can induce protein mistargeting and, in turn, threaten cellular protein homeostasis. Current methods for measuring protein mistargeting are difficult to translate to living cells, and thus the role of cellular signaling networks in stress-dependent protein mistargeting processes, such as ER pre-emptive quality control (ER pQC), is difficult to parse. Herein, we use genetically encoded peroxidases to characterize protein import into the endoplasmic reticulum (ER). We show that the ERHRP/cytAPEX pair provides good selectivity and sensitivity for both multiplexed protein labeling and for identifying protein mistargeting, using the known ER pQC substrate transthyretin (TTR). Although ERHRP labeling induces formation of detergent-resistant TTR aggregates, this is minimized by using low ERHRP expression, without loss of labeling efficiency. cytAPEX labeling recovers TTR that is mistargeted as a consequence of Sec61 inhibition or ER stress-induced ER pQC. Furthermore, we discover that stress-free activation of the ER stress-associated transcription factor ATF6 recapitulates the TTR import deficiency of ER pQC. Hence, proximity labeling is an effective strategy for characterizing factors that influence ER protein import in living cells.
    DOI:  https://doi.org/10.1021/acschembio.2c00405
  6. Biophys Chem. 2022 Apr 29. pii: S0301-4622(22)00063-1. [Epub ahead of print]287 106821
    Protein folding in vitro and in the cell: From a solitary journey to a team effort.
    Miranda F Mecha, Rachel B Hutchinson, Jung Ho Lee, Silvia Cavagnero.
      Correct protein folding is essential for the health and function of living organisms. Yet, it is not well understood how unfolded proteins reach their native state and avoid aggregation, especially within the cellular milieu. Some proteins, especially small, single-domain and apparent two-state folders, successfully attain their native state upon dilution from denaturant. Yet, many more proteins undergo misfolding and aggregation during this process, in a concentration-dependent fashion. Once formed, native and aggregated states are often kinetically trapped relative to each other. Hence, the early stages of protein life are absolutely critical for proper kinetic channeling to the folded state and for long-term solubility and function. This review summarizes current knowledge on protein folding/aggregation mechanisms in buffered solution and within the bacterial cell, highlighting early stages. Remarkably, teamwork between nascent chain, ribosome, trigger factor and Hsp70 molecular chaperones enables all proteins to overcome aggregation propensities and reach a long-lived bioactive state.
    Keywords:  Aggregation; Chaperones; Cotranslational folding; Energy landscapes; Kinetic trapping; Ribosome
    DOI:  https://doi.org/10.1016/j.bpc.2022.106821
  7. EMBO Mol Med. 2022 Jun 07. e15851
    Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
    Chunyue Liu, Zixing Fu, Shanshan Wu, Xiaosong Wang, Shengrong Zhang, Chu Chu, Yuan Hong, Wenbo Wu, Shengqi Chen, Yueqing Jiang, Yang Wu, Yongbo Song, Yan Liu, Xing Guo.
      Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.
    Keywords:  Huntington's disease; heat shock transcription factor 1; human striatal organoids; mitochondrial DNA; single-stranded DNA-binding protein 1
    DOI:  https://doi.org/10.15252/emmm.202215851
  8. Nat Rev Mol Cell Biol. 2022 Jun 07.
    End of the road: from the ER to the proteasome.
    James A Olzmann.
      
    DOI:  https://doi.org/10.1038/s41580-022-00504-8
  9. Essays Biochem. 2022 Jun 09. pii: EBC20210060. [Epub ahead of print]
    The emerging roles of deubiquitinases in plant proteostasis.
    Michael J Skelly.
      Proper regulation of protein homeostasis (proteostasis) is essential for all organisms to survive. A diverse range of post-translational modifications (PTMs) allow precise control of protein abundance, function and cellular localisation. In eukaryotic cells, ubiquitination is a widespread, essential PTM that regulates most, if not all cellular processes. Ubiquitin is added to target proteins via a well-defined enzymatic cascade involving a range of conjugating enzymes and ligases, while its removal is catalysed by a class of enzymes known as deubiquitinases (DUBs). Many human diseases have now been linked to DUB dysfunction, demonstrating the importance of these enzymes in maintaining cellular function. These findings have led to a recent explosion in studying the structure, molecular mechanisms and physiology of DUBs in mammalian systems. Plant DUBs have however remained relatively understudied, with many DUBs identified but their substrates, binding partners and the cellular pathways they regulate only now beginning to emerge. This review focuses on the most recent findings in plant DUB biology, particularly on newly identified DUB substrates and how these offer clues to the wide-ranging roles that DUBs play in the cell. Furthermore, the future outlook on how new technologies in mammalian systems can accelerate the plant DUB field forward is discussed.
    Keywords:  deubiquitinase; plant biology; post translational modification; proteostasis; ubiquitin
    DOI:  https://doi.org/10.1042/EBC20210060
  10. PLoS Genet. 2022 Jun 06. 18(6): e1009978
    Tissue-specific inhibition of protein sumoylation uncovers diverse SUMO functions during C. elegans vulval development.
    Aleksandra Fergin, Gabriel Boesch, Nadja R Greter, Simon Berger, Alex Hajnal.
      The sumoylation (SUMO) pathway is involved in a variety of processes during C. elegans development, such as gonadal and vulval fate specification, cell cycle progression and maintenance of chromosome structure. The ubiquitous expression and pleiotropic effects have made it difficult to dissect the tissue-specific functions of the SUMO pathway and identify its target proteins. To overcome these challenges, we have established tools to block protein sumoylation and degrade sumoylated target proteins in a tissue-specific and temporally controlled manner. We employed the auxin-inducible protein degradation system (AID) to down-regulate the SUMO E3 ligase GEI-17 or the SUMO ortholog SMO-1, either in the vulval precursor cells (VPCs) or in the gonadal anchor cell (AC). Our results indicate that the SUMO pathway acts in multiple tissues to control different aspects of vulval development, such as AC positioning, basement membrane (BM) breaching, VPC fate specification and morphogenesis. In particular, inhibition of protein sumoylation in the VPCs resulted in abnormal toroid formation and ectopic cell fusions during vulval morphogenesis. In particular, sumoylation of the ETS transcription factor LIN-1 at K169 is necessary for the proper contraction of the ventral vulA toroids. Thus, the SUMO pathway plays several distinct roles throughout vulval development.
    DOI:  https://doi.org/10.1371/journal.pgen.1009978
  11. Biol Futur. 2022 Jun 07.
    Autophagy is required for spermatogonial differentiation in the Drosophila testis.
    Virginia B Varga, Dóra Schuller, Fanni Szikszai, Janka Szinyákovics, Gina Puska, Tibor Vellai, Tibor Kovács.
      Autophagy is a conserved, lysosome-dependent catabolic process of eukaryotic cells which is involved in cellular differentiation. Here, we studied its specific role in the differentiation of spermatogonial cells in the Drosophila testis. In the apical part of the Drosophila testis, there is a niche of germline stem cells (GSCs), which are connected to hub cells. Hub cells emit a ligand for bone morhphogenetic protein (BMP)-mediated signalling that represses Bam (bag of marbles) expression in GSCs to maintain them in an undifferentiated state. GSCs divide asymmetrically, and one of the daughter cells differentiates into a gonialblast, which eventually generates a cluster of spermatogonia (SG) by mitoses. Bam is active in SG, and defects in Bam function arrest these cells at mitosis. We show that BMP signalling represses autophagy in GSCs, but upregulates the process in SG. Inhibiting autophagy in SG results in an overproliferating phenotype similar to that caused by bam mutations. Furthermore, Bam deficiency leads to a failure in downstream mechanisms of the autophagic breakdown. These results suggest that the BMP-Bam signalling axis regulates developmental autophagy in the Drosophila testis, and that acidic breakdown of cellular materials is required for spermatogonial differentiation.
    Keywords:  Autophagy; BMP signalling pathway; Differentiation; Drosophila; Lysosome biogenesis; Stem cell
    DOI:  https://doi.org/10.1007/s42977-022-00122-7
  12. J Membr Biol. 2022 Jun 07.
    Amyloids on Membrane Interfaces: Implications for Neurodegeneration.
    Amaresh Kumar Mahakud, Jafarulla Shaikh, V V Rifa Iqbal, Abhinav Gupta, Anuj Tiwari, Mohammed Saleem.
      Membrane interfaces are vital for various cellular processes, and their involvement in neurodegenerative disorders such as Alzheimer's and Parkinson's disease has taken precedence in recent years. The amyloidogenic proteins associated with neurodegenerative diseases interact with the neuronal membrane through various means, which has implications for both the onset and progression of the disease. The parameters that regulate the interaction between the membrane and the amyloids remain poorly understood. The review focuses on the various aspects of membrane interactions of amyloids, particularly amyloid-β (Aβ) peptides and Tau involved in Alzheimer's and α-synuclein involved in Parkinson's disease. The genetic, cell biological, biochemical, and biophysical studies that form the basis for our current understanding of the membrane interactions of Aβ peptides, Tau, and α-synuclein are discussed.
    Keywords:  Amyloid beta (Aβ); Intrinsically disordered proteins (IDP); Neuronal membrane; Protein aggregation; Tau; α-Synuclein
    DOI:  https://doi.org/10.1007/s00232-022-00245-x
  13. Nucleic Acids Res. 2022 Jun 10. pii: gkac484. [Epub ahead of print]
    Identifying ribosome heterogeneity using ribosome profiling.
    Ferhat Alkan, Oscar G Wilkins, Santiago Hernández-Pérez, Sofia Ramalho, Joana Silva, Jernej Ule, William J Faller.
      Recent studies have revealed multiple mechanisms that can lead to heterogeneity in ribosomal composition. This heterogeneity can lead to preferential translation of specific panels of mRNAs, and is defined in large part by the ribosomal protein (RP) content, amongst other things. However, it is currently unknown to what extent ribosomal composition is heterogeneous across tissues, which is compounded by a lack of tools available to study it. Here we present dripARF, a method for detecting differential RP incorporation into the ribosome using Ribosome Profiling (Ribo-seq) data. We combine the 'waste' rRNA fragment data generated in Ribo-seq with the known 3D structure of the human ribosome to predict differences in the composition of ribosomes in the material being studied. We have validated this approach using publicly available data, and have revealed a potential role for eS25/RPS25 in development. Our results indicate that ribosome heterogeneity can be detected in Ribo-seq data, providing a new method to study this phenomenon. Furthermore, with dripARF, previously published Ribo-seq data provides a wealth of new information, allowing the identification of RPs of interest in many disease and normal contexts. dripARF is available as part of the ARF R package and can be accessed through https://github.com/fallerlab/ARF.
    DOI:  https://doi.org/10.1093/nar/gkac484
  14. Neurochem Int. 2022 May 31. pii: S0197-0186(22)00087-0. [Epub ahead of print]158 105362
    Structures of tau and α-synuclein filaments from brains of patients with neurodegenerative diseases.
    Fuyuki Kametani, Masato Hasegawa.
      Intracellular accumulations and aggregates of abnormal protein, consisting of amyloid-like fibrils, are common neuropathological features of many neurodegenerative diseases. The distributions and spreading of these pathological proteins are closely correlated with clinical symptoms and progression. Recent evidence supports the idea that template-mediated amplification of amyloid-like fibrils and intracellular propagation of fibril seeds are the main mechanisms by which pathological features spread along the neural circuits in the brain. Here, we review recent developments in the structural analysis of amyloid-like fibrils from brains of patients with various types of tauopathy and α-synucleinopathy, focusing on cryo-electron microscopy and mass analysis, and we discuss their relevance to the mechanisms of template-mediated amplification and intracellular propagation.
    Keywords:  Cryo-electron microscopy; Filament core structure; Inclusion body; Tauopathy; α-Synucleinopathy
    DOI:  https://doi.org/10.1016/j.neuint.2022.105362
  15. Stem Cell Res Ther. 2022 Jun 03. 13(1): 236
    Hyperthermia increases HSP production in human PDMCs by stimulating ROS formation, p38 MAPK and Akt signaling, and increasing HSF1 activity.
    Ju-Fang Liu, Po-Chun Chen, Thai-Yen Ling, Chun-Han Hou.
      BACKGROUND: Human placenta-derived multipotent cells (hPDMCs) are isolated from a source uncomplicated by ethical issues and are ideal for therapeutic applications because of their capacity for multilineage differentiation and proven immunosuppressive properties. It is known that heat shock preconditioning induces the upregulation of heat shock proteins (HSPs), which enhance survival and engraftment of embryonic stem cells (ESCs) during transplantation in live animal models, although whether heat shock preconditioning has the same effects in hPDMCs is unclear.METHODS: The hPDMCs were isolated from placenta of healthy donors. The cells were treated with heat shock (43 °C, 15 min), followed by evaluation of cell viability. Furthermore, the HSPs expression was assessed by Western blot, qPCR. The reactive oxygen species (ROS) production and signal pathway activation were determined by flow cytometry and Western blot, respectively. The regulatory pathways involved in HSPs expression were examined by pretreatment with chemical inhibitors, and siRNAs of MAPK, Akt, and heat shock factor 1 (HSF1), followed by determination of HSPs expression.
    RESULTS: This study demonstrates that heat shock treatment induced ROS generation and HPSs expression in hPDMCs. Heat shock stimulation also increased p38 MAPK and Akt phosphorylation. These effects were reduced by inhibitors of ROS, p38 MAPK and Akt. Moreover, we found that heat shock treatment enhanced nuclear translocation of the HSF1 in hPDMCs, representing activation of HSF1. Pretreatment of hPDMCs with ROS scavengers, SB203580 and Akt inhibitors also reduced the translocation of HSF1 induced by heat shock.
    CONCLUSIONS: Our data indicate that heat shock acts via ROS to activate p38 MAPK and Akt signaling, which subsequently activates HSF1, leading to HSP activation and contributing to the protective role of hPDMCs.
    Keywords:  Heat shock; Heat shock proteins (HSPs); hPDMCs (hPDMCs)
    DOI:  https://doi.org/10.1186/s13287-022-02885-1
  16. EMBO J. 2022 Jun 07. e109958
    Arabidopsis HEAT SHOCK FACTOR BINDING PROTEIN is required to limit meiotic crossovers and HEI10 transcription.
    Juhyun Kim, Jihye Park, Heejin Kim, Namil Son, Eun-Jung Kim, Jaeil Kim, Dohwan Byun, Youngkyung Lee, Yeong Mi Park, Divyashree C Nageswaran, Pallas Kuo, Teresa Rose, Tuong Vi T Dang, Ildoo Hwang, Christophe Lambing, Ian R Henderson, Kyuha Choi.
      The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a fluorescent crossover reporter in Arabidopsis thaliana, we identify heat shock factor binding protein (HSBP) as a repressor of HEI10 transcription and crossover numbers. Using genome-wide crossover mapping and cytogenetics, we show that hsbp mutations or meiotic HSBP knockdowns increase ZMM-dependent crossovers toward the telomeres, mirroring the effects of HEI10 overexpression. Through RNA sequencing, DNA methylome, and chromatin immunoprecipitation analysis, we reveal that HSBP is required to repress HEI10 transcription by binding with heat shock factors (HSFs) at the HEI10 promoter and maintaining DNA methylation over the HEI10 5' untranslated region. Our findings provide insights into how the temperature response regulator HSBP restricts meiotic HEI10 transcription and crossover number by attenuating HSF activity.
    Keywords:  Crossover; HEI10; HSBP; HSF; meiosis
    DOI:  https://doi.org/10.15252/embj.2021109958
  17. Cell Stem Cell. 2022 Jun 02. pii: S1934-5909(22)00200-4. [Epub ahead of print]29(6): 918-932.e8
    Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons.
    Lucia S Capano, Chihiro Sato, Elena Ficulle, Anan Yu, Kanta Horie, Ji-Sun Kwon, Kyle F Burbach, Nicolas R Barthélemy, Susan G Fox, Celeste M Karch, Randall J Bateman, Henry Houlden, Richard I Morimoto, David M Holtzman, Karen E Duff, Andrew S Yoo.
      Tau is a microtubule-binding protein expressed in neurons, and the equal ratios between 4-repeat (4R) and 3-repeat (3R) isoforms are maintained in normal adult brain function. Dysregulation of 3R:4R ratio causes tauopathy, and human neurons that recapitulate tau isoforms in health and disease will provide a platform for elucidating pathogenic processes involving tau pathology. We carried out extensive characterizations of tau isoforms expressed in human neurons derived by microRNA-induced neuronal reprogramming of adult fibroblasts. Transcript and protein analyses showed that miR neurons expressed all six isoforms with the 3R:4R isoform ratio equivalent to that detected in human adult brains. Also, miR neurons derived from familial tauopathy patients with a 3R:4R ratio altering mutation showed increased 4R tau and the formation of insoluble tau with seeding activity. Our results collectively demonstrate the utility of miRNA-induced neuronal reprogramming to recapitulate endogenous tau regulation comparable with the adult brain in health and disease.
    Keywords:  4R tau; adult human neurons; insoluble tau; microRNA-induced neurons; neuronal reprogramming; tau isoform ratio; tau isoforms; tau seeding; tauopathy
    DOI:  https://doi.org/10.1016/j.stem.2022.04.018
  18. Stem Cell Res. 2022 Jun 01. pii: S1873-5061(22)00174-X. [Epub ahead of print]62 102825
    Generation of an induced pluripotent stem cell line (UCSCi002-A) from a patient with a variant in TARDBP gene associated with familial amyotrophic lateral sclerosis and frontotemporal dementia.
    Francesco Martello, Serena Lattante, Paolo Niccolò Doronzio, Amelia Conte, Giulia Bisogni, Daniela Orteschi, Marco Luigetti, Maria Alessandra Marrucci, Marcella Zollino, Mario Sabatelli, Giuseppe Marangi.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons. In 20% of cases, ALS appears in comorbidity with frontotemporal dementia (FTD). We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS/FTD patient. The patient had a familial form of the disease and a missense variant in TARDBP gene. We used an established protocol based on Sendai virus to reprogram fibroblasts. We confirmed the stemness and the pluripotency of the iPSC clones, thus generating embryoid bodies. We believe that the iPSC line carrying a TARDBP mutation could be a valuable tool to investigate TDP-43 proteinopathy linked to ALS.
    DOI:  https://doi.org/10.1016/j.scr.2022.102825
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