bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022–07–10
twelve papers selected by
Rich Giadone, Harvard University
  1. Molecular mechanisms of amyloid formation in living systems.
  2. Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
  3. Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases.
  4. The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation.
  5. Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.
  6. Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.
  7. Structure-specific amyloid precipitation in biofluids.
  8. Amyloid fil rouge from invertebrate up to human ageing: a focus on Alzheimer Disease.
  9. Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans.
  10. Living a longer life: unique lessons from the naked mole-rat blood system.
  11. A conversation on using chemical probes to study protein function in cells and organisms.
  12. Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson's in vivo models.
  1. Chem Sci. 2022 Jun 22. 13(24): 7080-7097
    Molecular mechanisms of amyloid formation in living systems.
    Tessa Sinnige.
      Fibrillar protein aggregation is a hallmark of a variety of human diseases. Examples include the deposition of amyloid-β and tau in Alzheimer's disease, and that of α-synuclein in Parkinson's disease. The molecular mechanisms by which soluble proteins form amyloid fibrils have been extensively studied in the test tube. These investigations have revealed the microscopic steps underlying amyloid formation, and the role of factors such as chaperones that modulate these processes. This perspective explores the question to what extent the mechanisms of amyloid formation elucidated in vitro apply to human disease. The answer is not yet clear, and may differ depending on the protein and the associated disease. Nevertheless, there are striking qualitative similarities between the aggregation behaviour of proteins in vitro and the development of the related diseases. Limited quantitative data obtained in model organisms such as Caenorhabditis elegans support the notion that aggregation mechanisms in vivo can be interpreted using the same biophysical principles established in vitro. These results may however be biased by the high overexpression levels typically used in animal models of protein aggregation diseases. Molecular chaperones have been found to suppress protein aggregation in animal models, but their mechanisms of action have not yet been quantitatively analysed. Several mechanisms are proposed by which the decline of protein quality control with organismal age, but also the intrinsic nature of the aggregation process may contribute to the kinetics of protein aggregation observed in human disease.
    DOI:  https://doi.org/10.1039/d2sc01278b
  2. EMBO J. 2022 Jul 06. e110501
    Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
    Kimberly Wolzak, Anna Nölle, Margherita Farina, Truus Em Abbink, Marjo S van der Knaap, Matthijs Verhage, Wiep Scheper.
      Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.
    Keywords:  ANG; HRI; PERK; neuron-specific; translational control
    DOI:  https://doi.org/10.15252/embj.2021110501
  3. Neural Regen Res. 2023 Jan;18(1): 111-112
    Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases.
    Bingwei Lu.
      
    DOI:  https://doi.org/10.4103/1673-5374.340404
  4. Exp Neurobiol. 2022 Jun 30. 31(3): 196-207
    The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation.
    Song Mi Han, Yu Jung Jang, Eun Young Kim, Sun Ah Park.
      Circadian disruption often involves a neurodegenerative disorder, such as Alzheimer's disease or frontotemporal dementia, which are characterized by intraneuronal tau accumulations. The altered sleep pattern and diurnal rhythms in these disorders are the results of tau pathology. The circadian disturbance in reverse is thought to develop and potentially aggravate the condition. However, the underlying mechanism is not fully understood. In this study, perturbed oscillations in BMAL1 , the core clock gene, were observed in P301S tau transgenic mice. Tau fractionation analysis of the hippocampus revealed profound fluctuations in soluble and insoluble tau protein levels that were in opposite directions to each other according to zeitgeber time. Interestingly, a diurnal oscillation was detected in the heat shock 70 kDa protein 1A (Hsp70) chaperone that was in-phase with soluble tau but out-of-phase with insoluble tau. Tau protein levels decreased in the soluble and insoluble fractions when Hsp70 was overexpressed in HEK293T cells. Transfection of the BMAL1 carrying vector was continual with the increase in Hsp70 expression and diminished tau protein levels, and it was effectively attenuated by the knockdown of Hsp70, suggesting that Bmal1 could modulate tau protein by Hsp70. Our results suggest that altered circadian oscillations affect tau status and solubility by modulating Hsp70 expression in an experimental model of tau pathology. These findings suggest Hsp70 as a possible pathogenic link between circadian disruption and aggravations of tau pathology.
    Keywords:  Circadian rhythm; Hsp70 heat-shock proteins; Tau protein; Tauopathies
    DOI:  https://doi.org/10.5607/en22019
  5. Front Aging Neurosci. 2022 ;14 892518
    Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.
    Chenxuan Zhao, Yong Liao, Abdul Rahaman, Vijay Kumar.
      Biological stress due to the aberrant buildup of misfolded/unfolded proteins in the endoplasmic reticulum (ER) is considered a key reason behind many human neurodegenerative diseases. Cells adapted to ER stress through the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by degeneration of the motor system. It has largely been known that ER stress plays an important role in the pathogenesis of ALS through the dysregulation of proteostasis. Moreover, accumulating evidence indicates that ER stress and UPR are important players in TDP-43 pathology. In this mini-review, the complex interplay between ER stress and the UPR in ALS and TDP-43 pathology will be explored by taking into account the studies from in vitro and in vivo models of ALS. We also discuss therapeutic strategies to control levels of ER stress and UPR signaling components that have contrasting effects on ALS pathogenesis.
    Keywords:  ALS; ER stress; TDP-43; UPR; pharmacological modulator
    DOI:  https://doi.org/10.3389/fnagi.2022.892518
  6. Sci Rep. 2022 Jul 07. 12(1): 11533
    Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.
    Kazuhiro Kunimasa, Chika Ikeda-Ishikawa, Yuri Tani, Satomi Tsukahara, Junko Sakurai, Yuka Okamoto, Masaru Koido, Shingo Dan, Akihiro Tomida.
      The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation.
    DOI:  https://doi.org/10.1038/s41598-022-15673-x
  7. Nat Chem. 2022 Jul 07.
    Structure-specific amyloid precipitation in biofluids.
    M Rodrigues, P Bhattacharjee, A Brinkmalm, D T Do, C M Pearson, S De, A Ponjavic, J A Varela, K Kulenkampff, I Baudrexel, D Emin, F S Ruggeri, J E Lee, A R Carr, T P J Knowles, H Zetterberg, T N Snaddon, S Gandhi, S F Lee, D Klenerman.
      The composition of soluble toxic protein aggregates formed in vivo is currently unknown in neurodegenerative diseases, due to their ultra-low concentration in human biofluids and their high degree of heterogeneity. Here we report a method to capture amyloid-containing aggregates in human biofluids in an unbiased way, a process we name amyloid precipitation. We use a structure-specific chemical dimer, a Y-shaped, bio-inspired small molecule with two capture groups, for amyloid precipitation to increase affinity. Our capture molecule for amyloid precipitation (CAP-1) consists of a derivative of Pittsburgh Compound B (dimer) to target the cross β-sheets of amyloids and a biotin moiety for surface immobilization. By coupling CAP-1 to magnetic beads, we demonstrate that we can target the amyloid structure of all protein aggregates present in human cerebrospinal fluid, isolate them for analysis and then characterize them using single-molecule fluorescence imaging and mass spectrometry. Amyloid precipitation enables unbiased determination of the molecular composition and structural features of the in vivo aggregates formed in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41557-022-00976-3
  8. Mech Ageing Dev. 2022 Jul 04. pii: S0047-6374(22)00087-2. [Epub ahead of print] 111705
    Amyloid fil rouge from invertebrate up to human ageing: a focus on Alzheimer Disease.
    Magda de Eguileor, Annalisa Grimaldi, Laura Pulze, Francesco Acquati, Cristina Morsiani, Miriam Capri.
      Amyloid fibrils and fibril-like structures are currently estimated to represent many different products of several genes in humans and play a key role in many types of proteinopathies, commonly associated with ageing process. They share the mutual feature of aggregation-prone proteins and the building up of molecular-supramolecular structure, such as inter-neuronal plaques in the brain of Alzheimer's Disease (AD) patients, characterized by an extraordinary strength. Noteworthy, this type of structure has been reported in different organisms, in particular in invertebrates. The aim of the current review is to focus on alpha and beta amyloids i.e., SAAs, SAP and APP, elucidating the structure and function of amyloid proteins in invertebrates (such as nematods, annelids, molluscs, insects, ascidians) and highlighting their striking pattern of functional conservation when compared to human amyloid-like fibrils, thus focusing on possible new studies and applications for innovative therapies, particularly for AD, the most common and worldwide type of dementia.
    Keywords:  Alzheimer Disease; age-related diseases; alpha-amyloid; amyloid fibril-like; beta-amyloid; invertebrate amyloid structures
    DOI:  https://doi.org/10.1016/j.mad.2022.111705
  9. Front Pharmacol. 2022 ;13 924862
    Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans.
    Amirthalingam Mohankumar, Duraisamy Kalaiselvi, Govindhan Thiruppathi, Sivaramakrishnan Muthusaravanan, Subramaniam Vijayakumar, Rahul Suresh, Shinkichi Tawata, Palanisamy Sundararaj.
      Transthyretin (TTR) is a homotetrameric protein found in human serum and is implicated in fatal inherited amyloidoses. Destabilization of native TTR confirmation resulting from mutation, environmental changes, and aging causes polymerization and amyloid fibril formation. Although several small molecules have been reported to stabilize the native state and inhibit TTR aggregation, prolonged use can cause serious side effects. Therefore, pharmacologically enhancing the degradation of TTR aggregates and kinetically stabilizing the native tetrameric structure with bioactive molecule(s) could be a viable therapeutic strategy to hinder the advancement of TTR amyloidoses. In this context, here we demonstrated α- and β-santalol, natural sesquiterpenes from sandalwood, as a potent TTR aggregation inhibitor and native state stabilizer using combined in vitro, in silico, and in vivo experiments. We found that α- and β-santalol synergize to reduce wild-type (WT) and Val30Met (V30M) mutant TTR aggregates in novel C. elegans strains expressing TTR fragments fused with a green fluorescent protein in body wall muscle cells. α- and β-Santalol extend the lifespan and healthspan of C. elegans strains carrying TTRWT::EGFP and TTRV30M::EGFP transgene by activating the SKN-1/Nrf2, autophagy, and proteasome. Moreover, α- and β-santalol directly interacted with TTR and reduced the flexibility of the thyroxine-binding cavity and homotetramer interface, which in turn increases stability and prevents the dissociation of the TTR tetramer. These data indicate that α- and β-santalol are the strong natural therapeutic intervention against TTR-associated amyloid diseases.
    Keywords:  Caenorhabditis elegans; familial amyloid polyneuropathy; santalol isomers; synergism; tetramer stabilizer; transthyretin
    DOI:  https://doi.org/10.3389/fphar.2022.924862
  10. EMBO J. 2022 Jul 04. e111759
    Living a longer life: unique lessons from the naked mole-rat blood system.
    Rebecca Andersson, Maria Carolina Florian.
      Analysis of functional deterioration of the blood system during ageing has been largely confined to the mouse and human system. In this issue, Emmrich et al (2022) report the first comprehensive characterisation of the haematopoietic system of the naked mole-rat (NMR), an exceptionally long-lived rodent, highlighting its unique features and uncovering potential strategies to sustain haematopoiesis during an extended lifetime.
    DOI:  https://doi.org/10.15252/embj.2022111759
  11. Nat Commun. 2022 Jul 05. 13(1): 3757
    A conversation on using chemical probes to study protein function in cells and organisms.
      
    DOI:  https://doi.org/10.1038/s41467-022-31271-x
  12. Life Sci Alliance. 2022 Nov;pii: e202201366. [Epub ahead of print]5(11):
    Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson's in vivo models.
    Merry Chen, Julie Vincent, Alexis Ezeanii, Saurabh Wakade, Shobha Yerigenahally, Danielle E Mor.
      Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of α-synuclein transmission and neurotoxicity remain poorly understood. Animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first Caenorhabditis elegans models in which feeding with α-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human α-synuclein expressed in the host, and an associated motor decline. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, or other enzymes involved in heparan sulfate proteoglycan synthesis, protected against PFF-induced α-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.
    DOI:  https://doi.org/10.26508/lsa.202201366
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