bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2021–11–14
eleven papers selected by
Rich Giadone, Harvard University
  1. Model Identifies Genetic Predisposition of Alzheimer's Disease as Key Decider in Cell Susceptibility to Stress.
  2. Emerging roles of N-linked glycosylation in brain physiology and disorders.
  3. A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets.
  4. Assessment of neurodegeneration and neuronal loss in aged 5XFAD mice.
  5. Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein.
  6. Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration.
  7. The Lack of Amyloidogenic Activity Is Persistent in Old WT and APPswe/PS1ΔE9 Mouse Retinae.
  8. Regulation of Hippo pathway by Hsp70-Bag3 complex: Bag3 modulates YAP phosphorylation and its nuclear translocation.
  9. An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation.
  10. Human iPSC-derived hippocampal spheroids: An innovative tool for stratifying Alzheimer disease patient-specific cellular phenotypes and developing therapies.
  11. Lack of Parkinsonian Pathology and Neurodegeneration in Mice After Long-Term Injections of a Proteasome Inhibitor in Olfactory Bulb and Amygdala.
  1. Int J Mol Sci. 2021 Nov 05. pii: 12001. [Epub ahead of print]22(21):
    Model Identifies Genetic Predisposition of Alzheimer's Disease as Key Decider in Cell Susceptibility to Stress.
    Ioanna C Stefani, François-Xavier Blaudin de Thé, Cleo Kontoravdi, Karen M Polizzi.
      Accumulation of unfolded/misfolded proteins in neuronal cells perturbs endoplasmic reticulum homeostasis, triggering a stress cascade called unfolded protein response (UPR), markers of which are upregulated in Alzheimer's disease (AD) brain specimens. We measured the UPR dynamic response in three human neuroblastoma cell lines overexpressing the wild-type and two familial AD (FAD)-associated mutant forms of amyloid precursor protein (APP), the Swedish and Swedish-Indiana mutations, using gene expression analysis. The results reveal a differential response to subsequent environmental stress depending on the genetic background, with cells overexpressing the Swedish variant of APP exhibiting the highest global response. We further developed a dynamic mathematical model of the UPR that describes the activation of the three branches of this stress response in response to unfolded protein accumulation. Model-based analysis of the experimental data suggests that the mutant cell lines experienced a higher protein load and subsequent magnitude of transcriptional activation compared to the cells overexpressing wild-type APP, pointing to higher susceptibility of mutation-carrying cells to stress. The model was then used to understand the effect of therapeutic agents salubrinal, lithium, and valproate on signalling through different UPR branches. This study proposes a novel integrated platform to support the development of therapeutics for AD.
    Keywords:  amyloid precursor protein; beta-amyloid; endoplasmic reticulum stress; mathematical modelling; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms222112001
  2. Trends Endocrinol Metab. 2021 Dec;pii: S1043-2760(21)00221-6. [Epub ahead of print]32(12): 980-993
    Emerging roles of N-linked glycosylation in brain physiology and disorders.
    Lindsey R Conroy, Tara R Hawkinson, Lyndsay E A Young, Matthew S Gentry, Ramon C Sun.
      N-linked glycosylation is a complex, co- and post-translational series of events that connects metabolism to signaling in almost all cells. Metabolic assembly of N-linked glycans spans multiple cellular compartments, and early N-linked glycan biosynthesis is a central mediator of protein folding and the unfolded protein response (UPR). In the brain, N-linked glycosylated proteins participate in a myriad of processes, from electrical gradients to neurotransmission. However, it is less clear how perturbations in N-linked glycosylation impact and even potentially drive aspects of neurological disorders. In this review, we discuss our current understanding of the metabolic origins of N-linked glycans in the brain, their role in modulating neuronal function, and how aberrant N-linked glycosylation can drive neurological disorders.
    Keywords:  Alzheimer’s disease; N-linked glycosylation; carbohydrate metabolism; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.tem.2021.09.006
  3. Sci Adv. 2021 Nov 12. 7(46): eabi8178
    A brain proteomic signature of incipient Alzheimer's disease in young APOE ε4 carriers identifies novel drug targets.
    Jackson A Roberts, Vijay R Varma, Yang An, Sudhir Varma, Julián Candia, Giovanna Fantoni, Vinod Tiwari, Carlos Anerillas, Andrew Williamson, Atsushi Saito, Tina Loeffler, Irene Schilcher, Ruin Moaddel, Mohammed Khadeer, Jacqueline Lovett, Toshiko Tanaka, Olga Pletnikova, Juan C Troncoso, David A Bennett, Marilyn S Albert, Kaiwen Yu, Mingming Niu, Vahram Haroutunian, Bin Zhang, Junmin Peng, Deborah L Croteau, Susan M Resnick, Myriam Gorospe, Vilhelm A Bohr, Luigi Ferrucci, Madhav Thambisetty.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abi8178
  4. STAR Protoc. 2021 Dec 17. 2(4): 100915
    Assessment of neurodegeneration and neuronal loss in aged 5XFAD mice.
    Liansheng Zhang, Jie Li, Anning Lin.
      Neuronal loss resulting from progressive neurodegeneration is a major pathological feature of Alzheimer's disease (AD). Here, we present a protocol to detect neurodegeneration, neuronal apoptosis, and neuronal loss in 5XFAD mouse strain, which is a well-established model for interrogating the molecular mechanism of neuronal death in AD. This protocol describes the use of the neurodegenerative marker Fluro-Jade C, cleaved caspase-3 immunofluorescent staining and Nissl staining for the analysis of neurodegeneration and neuronal loss in 5XFAD mice. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).
    Keywords:  Microscopy; Model Organisms; Molecular/Chemical Probes; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2021.100915
  5. Nat Commun. 2021 Nov 08. 12(1): 6447
    Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein.
    Elena Plessa, Lien P Chu, Sammy H S Chan, Oliver L Thomas, Anaïs M E Cassaignau, Christopher A Waudby, John Christodoulou, Lisa D Cabrita.
      During biosynthesis, proteins can begin folding co-translationally to acquire their biologically-active structures. Folding, however, is an imperfect process and in many cases misfolding results in disease. Less is understood of how misfolding begins during biosynthesis. The human protein, alpha-1-antitrypsin (AAT) folds under kinetic control via a folding intermediate; its pathological variants readily form self-associated polymers at the site of synthesis, leading to alpha-1-antitrypsin deficiency. We observe that AAT nascent polypeptides stall during their biosynthesis, resulting in full-length nascent chains that remain bound to ribosome, forming a persistent ribosome-nascent chain complex (RNC) prior to release. We analyse the structure of these RNCs, which reveals compacted, partially-folded co-translational folding intermediates possessing molten-globule characteristics. We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type. Its very modest structural differences suggests that the ribosome uniquely tempers the impact of deleterious mutations during nascent chain emergence. Following nascent chain release however, these co-translational folding intermediates guide post-translational folding outcomes thus suggesting that Z's misfolding is initiated from co-translational structure. Our findings demonstrate that co-translational folding intermediates drive how some proteins fold under kinetic control, and may thus also serve as tractable therapeutic targets for human disease.
    DOI:  https://doi.org/10.1038/s41467-021-26531-1
  6. Front Neurosci. 2021 ;15 702788
    Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration.
    Ben Boyarko, Vivian Hook.
      The human tau protein is implicated in a wide range of neurodegenerative "tauopathy" diseases, consisting of Alzheimer's disease (AD) and frontotemporal lobar degeneration which includes progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and FTLD-tau (frontotemporal dementia with parkinsonism caused by MAPT mutations). Tau gene transcripts in the human brain undergo alternative splicing to yield 6 different tau protein isoforms that are expressed in different ratios in neurodegeneration which result in tau pathology of paired-helical filaments, neurofibrillary tangles, and tau fibrillar aggregates with detrimental microtubule destabilization. Protease-mediated tau truncation is an important post-translational modification (PTM) which drives neurodegeneration in a tau fragment-dependent manner. While numerous tau fragments have been identified, knowledge of the proteolytic steps that convert each parent tau isoform into specific truncated tau fragments has not yet been fully defined. An improved understanding of the relationships between tau isoforms and their proteolytic processing to generate neurotoxic tau fragments is important to the field. This review evaluates tau isoform expression patterns including PTMs and mutations that influence proteolysis of tau to generate toxic fragments that drive cognitive deficits in AD and other tauopathy models. This assessment identifies the gap in the field on understanding the details of proteolytic steps used to convert each tau isoform into fragments. Knowledge of the processing mechanisms of tau isoforms can lead to new protease targeted drug strategies to prevent the formation of toxic tau fragments in tauopathy neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; frontotemporal dementia; mutations; neurotoxicity; protease; tau fragments; tau isoforms; tauopathies
    DOI:  https://doi.org/10.3389/fnins.2021.702788
  7. Int J Mol Sci. 2021 Oct 20. pii: 11344. [Epub ahead of print]22(21):
    The Lack of Amyloidogenic Activity Is Persistent in Old WT and APPswe/PS1ΔE9 Mouse Retinae.
    Sandrine Joly, Léa Rodriguez, Vincent Pernet.
      We have previously reported that vision decline was not associated with amyloidogenesis processing in aging C57BL/6J wild-type (WT) mice and in a mouse model of Alzheimer's disease, the APPswe/PS1ΔE9 transgenic mouse model (APP/PS1). This conclusion was drawn using middle-aged (10-13 months old) mice. Here, we hypothesized that compared with hippocampal and cortical neurons, the weak amyloidogenic activity of retinal neurons may result in a detectable release of amyloid β (Aβ) only in aged mice, i.e., between 14 and 24 months of age. The aim of the present study was thus to follow potential activity changes in the amyloidogenic and nonamyloidogenic pathways of young (4 months) and old (20-24 months) WT and APP/PS1 mice. Our results showed that in spite of retinal activity loss reported by electroretinogram (ERG) recordings, the level of amyloid beta precursor protein (APP) and its derivatives did not significantly vary in the eyes of old vs. young mice. Strikingly, the ectopic expression of human APPswe in APP/PS1 mice did not allow us to detect Aβ monomers at 23 months. In contrast, Aβ was observed in hippocampal and cortical tissues at this age but not at 4 months of life. In contrast, optic nerve transection-induced retinal ganglion cell injury significantly affected the level of retinal APP and the secretion of soluble APP alpha in the vitreous. Collectively, these results suggest that the amyloidogenic and nonamyloidogenic pathways are not involved in visual function decline in aging mice. In WT and APP/PS1 mice, it is proposed that retinal neurons do not have the capacity to secrete Aβ in contrast with other cortical and hippocampal neurons.
    Keywords:  Alzheimer’s disease; aging; electroretinogram; photoreceptors; retina
    DOI:  https://doi.org/10.3390/ijms222111344
  8. J Cell Sci. 2021 Nov 11. pii: jcs.259107. [Epub ahead of print]
    Regulation of Hippo pathway by Hsp70-Bag3 complex: Bag3 modulates YAP phosphorylation and its nuclear translocation.
    Simone Baldan, Anatoli B Meriin, Julia Yaglom, Ilya Alexandrov, Xaralabos Varelas, Zhi-Xiong Jim Xiao, Michael Y Sherman.
      Protein abnormalities can accelerate aging causing protein misfolding diseases, various adaptive responses have evolved to relieve proteotoxicity. To trigger these responses, cells must detect the buildup of aberrant proteins. Previously we demonstrated that the Hsp70-Bag3 (HB) complex senses the accumulation of defective ribosomal products, stimulating signaling pathways, such as stress kinases or the Hippo pathway kinase LATS1. Here, we studied how Bag3 regulates the ability for LATS1 to regulate its key downstream target YAP. In naïve cells, Bag3 recruited a complex of LATS1, YAP, and the scaffold AmotL2, which links LATS1 and YAP. Upon inhibition of proteasome, AmotL2 dissociated from Bag3, which prevented phosphorylation of YAP by LATS1 and led to consequent nuclear YAP localization together with Bag3. Mutations in Bag3 that enhanced its translocation into nucleus, also facilitated nuclear translocation of YAP. Interestingly, Bag3 also controlled YAP nuclear localization in response to cell density, indicating broader roles beyond proteotoxic signaling responses for Bag3 in the regulation of YAP. These data implicate Bag3 as a regulator of Hippo pathway signaling, and suggest mechanisms by which proteotoxic stress signals are propagated.
    Keywords:  Bag3; Lats1; proteotoxicity
    DOI:  https://doi.org/10.1242/jcs.259107
  9. Nat Commun. 2021 Nov 12. 12(1): 6558
    An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation.
    Pierre Sabatier, Christian M Beusch, Amir A Saei, Mike Aoun, Noah Moruzzi, Ana Coelho, Niels Leijten, Magnus Nordenskjöld, Patrick Micke, Diana Maltseva, Alexander G Tonevitsky, Vincent Millischer, J Carlos Villaescusa, Sandeep Kadekar, Massimiliano Gaetani, Kamilya Altynbekova, Alexander Kel, Per-Olof Berggren, Oscar Simonson, Karl-Henrik Grinnemo, Rikard Holmdahl, Sergey Rodin, Roman A Zubarev.
      Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro.
    DOI:  https://doi.org/10.1038/s41467-021-26879-4
  10. Stem Cell Reports. 2021 Nov 09. pii: S2213-6711(21)00527-0. [Epub ahead of print]16(11): 2838
    Human iPSC-derived hippocampal spheroids: An innovative tool for stratifying Alzheimer disease patient-specific cellular phenotypes and developing therapies.
    Yuriy Pomeshchik, Oxana Klementieva, Jeovanis Gil, Isak Martinsson, Marita Grønning Hansen, Tessa de Vries, Anna Sancho-Balsells, Kaspar Russ, Ekaterina Savchenko, Anna Collin, Ana Rita Vaz, Silvia Bagnoli, Benedetta Nacmias, Claire Rampon, Sandro Sorbi, Dora Brites, György Marko-Varga, Zaal Kokaia, Melinda Rezeli, Gunnar K Gouras, Laurent Roybon.
      
    DOI:  https://doi.org/10.1016/j.stemcr.2021.10.003
  11. Front Aging Neurosci. 2021 ;13 698979
    Lack of Parkinsonian Pathology and Neurodegeneration in Mice After Long-Term Injections of a Proteasome Inhibitor in Olfactory Bulb and Amygdala.
    Natalia Lopez-Gonzalez Del Rey, Tiziano Balzano, Lucia Martin-Rodriguez, Constanza Salinas-Rebolledo, Ines Trigo-Damas, Alejandro Rojas-Fernandez, Lydia Alvarez-Erviti, Javier Blesa.
      Proteinaceous inclusions, called Lewy bodies (LBs), are used as a pathological hallmark for Parkinson's disease (PD). Recent studies suggested a prion-like spreading mechanism for α-synucleinopathy where early neuropathological deposits occur, among others, in the olfactory bulb (OB) and amygdala. LBs contain insoluble α-synuclein and many other ubiquitinated proteins, suggesting a role of protein degradation system failure in PD pathogenesis. Therefore, we wanted to study the effects of a proteasomal inhibitor, lactacystin, on the aggregability and transmissibility of α-synuclein in the OB and amygdala. We performed injections of lactacystin in the OB and amygdala of wild-type mice. Motor behavior, markers of neuroinflammation, α-synuclein, and dopaminergic integrity were assessed by immunohistochemistry. Overall, there were no differences in the number of neurons and α-synuclein expression in these regions following injection of lactacystin into either the OB or amygdala. Microglial and astroglial labeling appeared to be correlated with surgery-induced inflammation or local effects of lactacystin. Consistent with the behavior and pathological findings, there was no loss of dopaminergic cell bodies in the substantia nigra and terminals in the striatum. Our data showed that long-term lactacystin injections in extra nigrostriatal regions may not mimic spreading aspects of PD and reinforce the special vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc).
    Keywords:  Parkinson’s disease; lactacystin; neurodegeneration; neuroinflammation; proteasome inhibition
    DOI:  https://doi.org/10.3389/fnagi.2021.698979
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