bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒06‒19
sixteen papers selected by
Rich Giadone
Harvard University
  1. Praja1 RING-finger E3 ubiquitin ligase is a common suppressor of neurodegenerative disease-associated protein aggregation.
  2. The Role of Ubiquitin in Regulating Stress Granule Dynamics.
  3. Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms.
  4. Role of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance.
  5. Measuring biological age using omics data.
  6. Structural remodeling of ribosome associated Hsp40-Hsp70 chaperones during co-translational folding.
  7. ERp57 Chaperon Protein Protects Neuronal Cells from Aβ-induced toxicity.
  8. Novel molecular targets and mechanisms for neuroprotective modulation in neurodegenerative disorders.
  9. Preprint Highlight: Transcriptomic changes highly similar to Alzheimer's disease are observed in a subpopulation of individuals during normal brain aging.
  10. Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity.
  11. Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer's tau pathology.
  12. Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology.
  13. Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase.
  14. Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells.
  15. Chaperonins, collaborations, and challenging dogmas: An interview with Dr. Arthur L. Horwich.
  16. Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology.
  1. Neuropathology. 2022 Jun 14.
    Praja1 RING-finger E3 ubiquitin ligase is a common suppressor of neurodegenerative disease-associated protein aggregation.
    Kazuhiko Watabe, Motoko Niida-Kawaguchi, Mari Tada, Yoichiro Kato, Makiko Murata, Kunikazu Tanji, Koichi Wakabayashi, Mitsunori Yamada, Akiyoshi Kakita, Noriyuki Shibata.
      The formation of misfolded protein aggregates is one of the pathological hallmarks of neurodegenerative diseases. We have previously demonstrated the cytoplasmic aggregate formation of adenovirally expressed transactivation response DNA-binding protein of 43 kDa (TDP-43), the main constituent of neuronal cytoplasmic aggregates in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), in cultured neuronal cells under the condition of proteasome inhibition. The TDP-43 aggregate formation was markedly suppressed by co-infection of adenoviruses expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response, and Praja1 RING-finger E3 ubiquitin ligase (PJA1) located downstream of the HSF1 pathway. In the present study, we examined other reportedly known E3 ubiquitin ligases for TDP-43, i.e. Parkin, RNF112 and RNF220, but failed to find their suppressive effects on neuronal cytoplasmic TDP-43 aggregate formation, although they all bind to TDP-43 as verified by co-immunoprecipitation. In contrast, PJA1 also binds to adenovirally expressed wild-type and mutated fused in sarcoma, superoxide dismutase 1, α-synuclein and ataxin-3, and huntingtin polyglutamine proteins in neuronal cultures and suppressed the aggregate formation of these proteins. These results suggest that PJA1 is a common sensing factor for aggregate-prone proteins to counteract their aggregation propensity, and could be a potential therapeutic target for neurodegenerative diseases that include ALS, FTLD, Parkinson's disease and polyglutamine diseases.
    Keywords:  Praja1; fused in sarcoma; superoxide dismutase 1; transactivation response DNA-binding protein of 43 kDa; α-synuclein
    DOI:  https://doi.org/10.1111/neup.12840
  2. Front Physiol. 2022 ;13 910759
    The Role of Ubiquitin in Regulating Stress Granule Dynamics.
    Laura J Krause, Maria G Herrera, Konstanze F Winklhofer.
      Stress granules (SGs) are dynamic, reversible biomolecular condensates, which assemble in the cytoplasm of eukaryotic cells under various stress conditions. Formation of SGs typically occurs upon stress-induced translational arrest and polysome disassembly. The increase in cytoplasmic mRNAs triggers the formation of a protein-RNA network that undergoes liquid-liquid phase separation when a critical interaction threshold has been reached. This adaptive stress response allows a transient shutdown of several cellular processes until the stress is removed. During the recovery from stress, SGs disassemble to re-establish cellular activities. Persistent stress and disease-related mutations in SG components favor the formation of aberrant SGs that are impaired in disassembly and prone to aggregation. Recently, posttranslational modifications of SG components have been identified as major regulators of SG dynamics. Here, we summarize new insights into the role of ubiquitination in affecting SG dynamics and clearance and discuss implications for neurodegenerative diseases linked to aberrant SG formation.
    Keywords:  FUS; G3BP; LLPS; SUMO; TDP-43; VCP/p97; ubiquitin
    DOI:  https://doi.org/10.3389/fphys.2022.910759
  3. Front Neurosci. 2022 ;16 858524
    Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms.
    Katie Peppercorn, Torsten Kleffmann, Owen Jones, Stephanie Hughes, Warren Tate.
      Secreted amyloid precursor protein alpha (sAPPα) processed from a parent human brain protein, APP, can modulate learning and memory. It has potential for development as a therapy preventing, delaying, or even reversing Alzheimer's disease. In this study a comprehensive analysis to understand how it affects the transcriptome and proteome of the human neuron was undertaken. Human inducible pluripotent stem cell (iPSC)-derived glutamatergic neurons in culture were exposed to 1 nM sAPPα over a time course and changes in the transcriptome and proteome were identified with RNA sequencing and Sequential Window Acquisition of All THeoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS), respectively. A large subset (∼30%) of differentially expressed transcripts and proteins were functionally involved with the molecular biology of learning and memory, consistent with reported links of sAPPα to memory enhancement, as well as neurogenic, neurotrophic, and neuroprotective phenotypes in previous studies. Differentially regulated proteins included those encoded in previously identified Alzheimer's risk genes, APP processing related proteins, proteins involved in synaptogenesis, neurotransmitters, receptors, synaptic vesicle proteins, cytoskeletal proteins, proteins involved in protein and organelle trafficking, and proteins important for cell signalling, transcriptional splicing, and functions of the proteasome and lysosome. We have identified a complex set of genes affected by sAPPα, which may aid further investigation into the mechanism of how this neuroprotective protein affects memory formation and how it might be used as an Alzheimer's disease therapy.
    Keywords:  APP; Alzheimer’s disease; amyloid beta (A4) precursor protein; human neuron; memory; proteome; sAPPα; transcriptome
    DOI:  https://doi.org/10.3389/fnins.2022.858524
  4. Mol Neurobiol. 2022 Jun 14.
    Role of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance.
    Subhashree Sahoo, Amrita Arpita Padhy, Varsha Kumari, Parul Mishra.
      Synuclein aggregation in neuronal cells is the primary underlying cause of synucleinopathies. Changes in gene expression patterns, structural modifications, and altered interactions with other cellular proteins often trigger aggregation of α-synuclein, which accumulates as oligomers or fibrils in Lewy bodies. Although fibrillar forms of α-synuclein are primarily considered pathological, recent studies have revealed that even the intermediate states of aggregates are neurotoxic, complicating the development of therapeutic interventions. Autophagy and ubiquitin-proteasome pathways play a significant role in maintaining the soluble levels of α-synuclein inside cells; however, the heterogeneous nature of the aggregates presents a significant bottleneck to its degradation by these cellular pathways. With studies focused on identifying the proteins that modulate synuclein aggregation and clearance, detailed mechanistic insights are emerging about the individual and synergistic effects of these degradation pathways in regulating soluble α-synuclein levels. In this article, we discuss the impact of α-synuclein aggregation on autophagy-lysosome and ubiquitin-proteasome pathways and the therapeutic strategies that target various aspects of synuclein aggregation or degradation via these pathways. Additionally, we also highlight the natural and synthetic compounds that have shown promise in alleviating the cellular damage caused due to synuclein aggregation.
    Keywords:  Aggregate clearance; Autophagy; Chaperone-mediated autophagy; Neurodegenerative diseases; Oligomers; Parkinson’s disease; Proteasome; Small molecules; Synucleinopathies; Ubiquitin; α-Synuclein
    DOI:  https://doi.org/10.1007/s12035-022-02897-1
  5. Nat Rev Genet. 2022 Jun 17.
    Measuring biological age using omics data.
    Jarod Rutledge, Hamilton Oh, Tony Wyss-Coray.
      Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.
    DOI:  https://doi.org/10.1038/s41576-022-00511-7
  6. Nat Commun. 2022 Jun 14. 13(1): 3410
    Structural remodeling of ribosome associated Hsp40-Hsp70 chaperones during co-translational folding.
    Yan Chen, Bin Tsai, Ningning Li, Ning Gao.
      Ribosome associated complex (RAC), an obligate heterodimer of HSP40 and HSP70 (Zuo1 and Ssz1 in yeast), is conserved in eukaryotes and functions as co-chaperone for another HSP70 (Ssb1/2 in yeast) to facilitate co-translational folding of nascent polypeptides. Many mechanistic details, such as the coordination of one HSP40 with two HSP70s and the dynamic interplay between RAC-Ssb and growing nascent chains, remain unclear. Here, we report three sets of structures of RAC-containing ribosomal complexes isolated from Saccharomyces cerevisiae. Structural analyses indicate that RAC on the nascent-chain-free ribosome is in an autoinhibited conformation, and in the presence of a nascent chain at the peptide tunnel exit (PTE), RAC undergoes large-scale structural remodeling to make Zuo1 J-Domain more accessible to Ssb. Our data also suggest a role of Zuo1 in orienting Ssb-SBD proximal to the PTE for easy capture of the substrate. Altogether, in accordance with previous data, our work suggests a sequence of structural remodeling events for RAC-Ssb during co-translational folding, triggered by the binding and passage of growing nascent chain from one to another.
    DOI:  https://doi.org/10.1038/s41467-022-31127-4
  7. J Neurochem. 2022 Jun 14.
    ERp57 Chaperon Protein Protects Neuronal Cells from Aβ-induced toxicity.
    Daniel Di Risola, Daniela Ricci, Ilaria Marrocco, Flavia Giamogante, Maddalena Grieco, Antonio Francioso, Aldrin Vasco-Vidal, Patrizia Mancini, Gianni Colotti, Luciana Mosca, Fabio Altieri.
      Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-β peptide (Aβ) in the form of senile plaques. Aβ can cause neurodegeneration and disrupt cognitive functions by several mechanisms, including oxidative stress. ERp57 is a protein disulfide isomerase involved in the cellular stress response and known to be present in the cerebrospinal fluid of normal individuals as a complex with Aβ peptides, suggesting that it may be a carrier protein which prevents aggregation of Aβ. Although several studies show ERp57 involvement in neurodegenerative diseases, no clear mechanism of action has been identified thus far. In this work we gain insights into the interaction of Aβwith ERp57, with a special focus on the contribution of ERp57 to the defence system of the cell. Here we show that recombinant ERp57 directly interacts with the Aβ25-35 fragment in vitro with high affinityvia two in silico-predicted main sites of interaction. Furthermore, we used human neuroblastoma cells to show that short-term Aβ25-35 treatment induces ERp57 decrease in intracellular protein levels, different intracellular localization and ERp57 secretion in the cultured medium. Finally, we demonstrate that recombinant ERp57 counteracts the toxic effects of Aβ25-35 and restores cellular viability, by preventing Aβ25-35 aggregation. Overall, the present study shows thatextracellular ERp57 can exert a protective effect from Aβ toxicity and highlights it as a possible therapeutic tool in the treatment of AD.
    Keywords:  Alzheimer’s disease; Amyloid beta25-35; ER stress; ERp57; PDIA3
    DOI:  https://doi.org/10.1111/jnc.15655
  8. Cent Nerv Syst Agents Med Chem. 2022 Jun 16.
    Novel molecular targets and mechanisms for neuroprotective modulation in neurodegenerative disorders.
    Aala Azari, Amin Goodarzi, Behrouz Jafarkhani, Mohammad Eghbali, Zohreh Karimi, Seyed Sajad Hosseini Balef, Hamid Irannejad.
      BACKGROUND: Neuronal death underlies the symptoms of several human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis that their precise pathophysiology have not yet been elucidated. According to various studies the prohibition is the best therapy with neuroprotective approaches which are advanced and safe methods.METHODS: This review summarizes some of the already-known and newly emerged neuroprotective targets and strategies that their experimental effects have been reported. Accordingly, literature was studied from 2000 to 2021 and appropriate articles were searched in Google Scholar and Scopus with the keywords given in the Keywords section of the current review.
    RESULTS: Lewy bodies are the histopathologic characteristics of neurodegenerative disorders and are protein-rich intracellular deposits in which Alpha-Synuclein is its major protein. Alpha-Synuclein's toxic potential provides a compelling rationale for therapeutic strategies aimed at decreasing its burden in neuronal cells through numerous pathways including ubiquitin-proteasome system and autophagy-lysosome Pathway, proteolytic breakdown via cathepsin D, kallikrein-6 (neurosin), calpain-1 or MMP9, heat shock proteins, and proteolysis targeting chimera which consists of a target protein ligand and an E3 ubiquitin ligase (E3) followed by target protein ubiquitination (PROTACs). Other targets that have been noticed recently are the mutant huntingtin, tau proteins and glycogen synthase kinase 3β that their accumulation proceeds extensive neuronal damage and up to the minute approach such as Proteolysis Targeting Chimera promotes its degradation in cells. As various studies demonstrated that Mendelian gene mutations can result into the neurodegenerative diseases, additional target that has gained much interest is epigenetics such as mutation, phosphodiesterase, RNA binding proteins and Nuclear respiratory factor 1.
    CONCLUSION: The novel molecular targets and new strategies compiled and introduced here can be used by scientists to design and discover more efficient small molecule drugs against the neurodegenerative diseases. And also the genes in which their mutations can lead to the α-synuclein aggregation or accumulation are discussed and considered a valuable information of epigenetics in dementia.
    Keywords:  Autophagy; Epigenetics; Heat Shock Protein; Neuroprotection; PROTAC; Ubiquitin-proteasome System; α-synuclein
    DOI:  https://doi.org/10.2174/1871524922666220616092132
  9. Mol Biol Cell. 2022 Jul 01. 33(8): mbcP22031007
    Preprint Highlight: Transcriptomic changes highly similar to Alzheimer's disease are observed in a subpopulation of individuals during normal brain aging.
    Dasfne Lee-Liu.
      
    DOI:  https://doi.org/10.1091/mbc.P22-03-1007
  10. Cell Syst. 2022 Jun 07. pii: S2405-4712(22)00223-X. [Epub ahead of print]
    Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity.
    Antoine E Roux, Chunlian Zhang, Jonathan Paw, José Zavala-Solorio, Evangelia Malahias, Twaritha Vijay, Ganesh Kolumam, Cynthia Kenyon, Jacob C Kimmel.
      Partial pluripotent reprogramming can reverse features of aging in mammalian cells, but the impact on somatic identity and the necessity of individual reprogramming factors remain unknown. Here, we used single-cell genomics to map the identity trajectory induced by partial reprogramming in multiple murine cell types and dissected the influence of each factor by screening all Yamanaka Factor subsets with pooled single-cell screens. We found that partial reprogramming restored youthful expression in adipogenic and mesenchymal stem cells but also temporarily suppressed somatic identity programs. Our pooled screens revealed that many subsets of the Yamanaka Factors both restore youthful expression and suppress somatic identity, but these effects were not tightly entangled. We also found that a multipotent reprogramming strategy inspired by amphibian regeneration restored youthful expression in myogenic cells. Our results suggest that various sets of reprogramming factors can restore youthful expression with varying degrees of somatic identity suppression. A record of this paper's Transparent Peer Review process is included in the supplemental information.
    Keywords:  aging; cell identity; reprogramming; single-cell RNA-seq
    DOI:  https://doi.org/10.1016/j.cels.2022.05.002
  11. Signal Transduct Target Ther. 2022 Jun 13. 7(1): 176
    Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimer's tau pathology.
    Shichao Huang, Zhen Zhang, Junwei Cao, Yongchun Yu, Gang Pei.
      The apolipoprotein E4 (APOE4) genotype is one of the strongest genetic risk factors for Alzheimer's disease (AD), and is generally believed to cause widespread pathological alterations in various types of brain cells. Here, we developed a novel engineering method of creating the chimeric human cerebral organoids (chCOs) to assess the differential roles of APOE4 in neurons and astrocytes. First, the astrogenic factors NFIB and SOX9 were introduced into induced pluripotent stem cells (iPSCs) to accelerate the induction of astrocytes. Then the above induced iPSCs were mixed and cocultured with noninfected iPSCs under the standard culturing condition of cerebral organoids. As anticipated, the functional astrocytes were detected as early as 45 days, and it helped more neurons matured in chCOs in comparation of the control human cerebral organoids (hCOs). More interestingly, this method enabled us to generate chCOs containing neurons and astrocytes with different genotypes, namely APOE3 or APOE4. Then, it was found in chCOs that astrocytic APOE4 already significantly promoted lipid droplet formation and cholesterol accumulation in neurons while both astrocytic and neuronal APOE4 contributed to the maximum effect. Most notably, we observed that the co-occurrence of astrocytic and neuronal APOE4 were required to elevate neuronal phosphorylated tau levels in chCOs while Aβ levels were increased in chCOs with neuronal APOE4. Altogether, our results not only revealed the essence of both neuronal and astrocytic APOE4 for tau pathology, but also suggested chCOs as a valuable pathological model for AD research and drug discovery.
    DOI:  https://doi.org/10.1038/s41392-022-01006-x
  12. Alzheimers Dement. 2022 Jun 14.
    Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology.
    Aurore Delvenne, Johan Gobom, Betty Tijms, Isabelle Bos, Lianne M Reus, Valerija Dobricic, Mara Ten Kate, Frans Verhey, Inez Ramakers, Philip Scheltens, Charlotte E Teunissen, Rik Vandenberghe, Jolien Schaeverbeke, Silvy Gabel, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Magda Tsolaki, Yvonne Freund-Levi, Simon Lovestone, Johannes Streffer, Frederik Barkhof, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Pieter Jelle Visser, Stephanie J B Vos.
      BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics.METHODS: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed.
    RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus.
    CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
    Keywords:  Alzheimer's disease; biomarkers; cerebrospinal fluid; mild cognitive impairment; pathophysiology; proteomics; suspected non-Alzheimer's disease pathophysiology; tau
    DOI:  https://doi.org/10.1002/alz.12713
  13. EMBO J. 2022 Jun 13. e110410
    Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase.
    Joseph George Beton, Jim Monistrol, Anne Wentink, Erin C Johnston, Anthony John Roberts, Bernd Gerhard Bukau, Bart W Hoogenboom, Helen R Saibil.
      Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of α-synuclein, huntingtin, or Tau. Disaggregation requires the ATPase activity of the constitutively expressed Hsp70 family member, Hsc70, together with the J domain protein DNAJB1 and the nucleotide exchange factor Apg2. Clustering of Hsc70 on the fibrils appears to be necessary for disassembly. Here we use atomic force microscopy to show that segments of in vitro assembled α-synuclein fibrils are first coated with chaperones and then undergo bursts of rapid, unidirectional disassembly. Cryo-electron tomography and total internal reflection fluorescence microscopy reveal fibrils with regions of densely bound chaperones, preferentially at one end of the fibre. Sub-stoichiometric amounts of Apg2 relative to Hsc70 dramatically increase recruitment of Hsc70 to the fibres, creating localised active zones that then undergo rapid disassembly at a rate of ~ 4 subunits per second. The observed unidirectional bursts of Hsc70 loading and unravelling may be explained by differences between the two ends of the polar fibre structure.
    Keywords:  atomic force microscopy; cryo-electron tomography; disaggregation; molecular chaperones
    DOI:  https://doi.org/10.15252/embj.2021110410
  14. Stem Cell Res Ther. 2022 Jun 17. 13(1): 260
    Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells.
    Sujoy Bhattacharya, Jinggang Yin, Weihong Huo, Edward Chaum.
      BACKGROUND: Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of age-related macular degeneration (AMD). However, a deeper understanding is required to determine the contribution of mitochondrial dysfunction and impaired mitochondrial autophagy (mitophagy) to RPE damage and AMD pathobiology. In this study, we model the impact of a prototypical systemic mitochondrial defect, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), in RPE health and homeostasis as an in vitro model for impaired mitochondrial bioenergetics.METHODS: We used induced pluripotent stem cells (iPSCs) derived from skin biopsies of MELAS patients (m.3243A > G tRNA leu mutation) with different levels of mtDNA heteroplasmy and differentiated them into RPE cells. Mitochondrial depletion of ARPE-19 cells (p0 cells) was also performed using 50 ng/mL ethidium bromide (EtBr) and 50 mg/ml uridine. Cell fusion of the human platelets with the p0 cells performed using polyethylene glycol (PEG)/suspension essential medium (SMEM) mixture to generate platelet/RPE "cybrids." Confocal microscopy, FLowSight Imaging cytometry, and Seahorse XF Mito Stress test were used to analyze mitochondrial function. Western Blotting was used to analyze expression of autophagy and mitophagy proteins.
    RESULTS: We found that MELAS iPSC-derived RPE cells exhibited key characteristics of native RPE. We observed heteroplasmy-dependent impairment of mitochondrial bioenergetics and reliance on glycolysis for generating energy in the MELAS iPSC-derived RPE. The degree of heteroplasmy was directly associated with increased activation of signal transducer and activator of transcription 3 (STAT3), reduced adenosine monophosphate-activated protein kinase α (AMPKα) activation, and decreased autophagic activity. In addition, impaired autophagy was associated with aberrant lysosomal function, and failure of mitochondrial recycling. The mitochondria-depleted p0 cells replicated the effects on autophagy impairment and aberrant STAT3/AMPKα signaling and showed reduced mitochondrial respiration, demonstrating phenotypic similarities between p0 and MELAS iPSC-derived RPE cells.
    CONCLUSIONS: Our studies demonstrate that the MELAS iPSC-derived disease models are powerful tools for dissecting the molecular mechanisms by which mitochondrial DNA alterations influence RPE function in aging and macular degeneration, and for testing novel therapeutics in patients harboring the MELAS genotype.
    Keywords:  AMPKα; Age-related macular degeneration; Autophagy flux; MELAS; Mitochondrial heteroplasmy; Mitophagy; PGC-1α; Prom1/CD133; Regenerative medicine; iPSC-derived retinal pigment epithelium
    DOI:  https://doi.org/10.1186/s13287-022-02937-6
  15. Mol Cell. 2022 Jun 16. pii: S1097-2765(22)00535-4. [Epub ahead of print]82(12): 2176-2178
    Chaperonins, collaborations, and challenging dogmas: An interview with Dr. Arthur L. Horwich.
      For our 25th anniversary of Molecular Cell, we talk to one of our original board members, Dr. Arthur L. Horwich, about the discovery of chaperones, the importance of challenging "dogmas," and the benefits of scientific collaboration. He also shares anecdotes from the early days of Molecular Cell, some of his favorite papers, and his advice for junior scientists.
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.037
  16. Brain Pathol. 2022 Jun 17. e13100
    Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology.
    Aya Murakami, Shunsuke Koga, Hiroaki Sekiya, Björn Oskarsson, Kevin Boylan, Leonard Petrucelli, Keith A Josephs, Dennis W Dickson.
      This study aimed to assess and compare the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate-to-severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old-ALS, n = 8), 64-74 years (middle-ALS, n = 23), and 63 years or younger (young-ALS, n = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS-CBS), were summarized. Sections of paraffin-embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho-TDP-43 immunohistochemistry. The burden of TDP-43 pathology was analyzed using digital image analysis. The TDP-43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old-ALS than in young-ALS and middle-ALS. TDP-43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS-CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP-43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic-predominant, age-related TDP-43 encephalopathy neuropathologic change.
    Keywords:  ALS; LATE; TDP-43; aging; limbic system; neuropathology
    DOI:  https://doi.org/10.1111/bpa.13100
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