bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–01–08
thirteen papers selected by
Rich Giadone, Harvard University
  1. The chaperone-assisted selective autophagy complex dynamics and dysfunctions.
  2. The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation.
  3. The Proteasome and Ageing.
  4. Hallmarks of aging: An expanding universe.
  5. Role of primary aging hallmarks in Alzheimer´s disease.
  6. The role of heat shock proteins in preventing amyloid toxicity.
  7. Mitochondria in Aging and Alzheimer's Disease: Focus on Mitophagy.
  8. Autophagy and longevity: Evolutionary hints from hyper-longevous mammals.
  9. Efficient generation of lower induced motor neurons by coupling Ngn2 expression with developmental cues.
  10. Ageing Skeletal Muscle: The Ubiquitous Muscle Stem Cell.
  11. Could an old brain be made young again?
  12. Differentiation-dependent changes in Lamin B1 dynamics and Lamin B Receptor localization.
  13. Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function.
  1. Autophagy. 2023 Jan 03. 1-23
    The chaperone-assisted selective autophagy complex dynamics and dysfunctions.
    Barbara Tedesco, Leen Vendredy, Vincent Timmerman, Angelo Poletti.
      Each protein must be synthesized with the correct amino acid sequence, folded into its native structure, and transported to a relevant subcellular location and protein complex. If any of these steps fail, the cell has the capacity to break down aberrant proteins to maintain protein homeostasis (also called proteostasis). All cells possess a set of well-characterized protein quality control systems to minimize protein misfolding and the damage it might cause. Autophagy, a conserved pathway for the degradation of long-lived proteins, aggregates, and damaged organelles, was initially characterized as a bulk degradation pathway. However, it is now clear that autophagy also contributes to intracellular homeostasis by selectively degrading cargo material. One of the pathways involved in the selective removal of damaged and misfolded proteins is chaperone-assisted selective autophagy (CASA). The CASA complex is composed of three main proteins (HSPA, HSPB8 and BAG3), essential to maintain protein homeostasis in muscle and neuronal cells. A failure in the CASA complex, caused by mutations in the respective coding genes, can lead to (cardio)myopathies and neurodegenerative diseases. Here, we summarize our current understanding of the CASA complex and its dynamics. We also briefly discuss how CASA complex proteins are involved in disease and may represent an interesting therapeutic target.Abbreviation ALP: autophagy lysosomal pathway; ALS: amyotrophic lateral sclerosis; AMOTL1: angiomotin like 1; ARP2/3: actin related protein 2/3; BAG: BAG cochaperone; BAG3: BAG cochaperone 3; CASA: chaperone-assisted selective autophagy; CMA: chaperone-mediated autophagy; DNAJ/HSP40: DnaJ heat shock protein family (Hsp40); DRiPs: defective ribosomal products; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK1/HRI: eukaryotic translation initiation factor 2 alpha kinase 1; GABARAP: GABA type A receptor-associated protein; HDAC6: histone deacetylase 6; HSP: heat shock protein; HSPA/HSP70: heat shock protein family A (Hsp70); HSP90: heat shock protein 90; HSPB8: heat shock protein family B (small) member 8; IPV: isoleucine-proline-valine; ISR: integrated stress response; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LATS1: large tumor suppressor kinase 1; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOC: microtubule organizing center; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; NFE2L2: NFE2 like bZIP transcription factor 2; PLCG/PLCγ: phospholipase C gamma; polyQ: polyglutamine; PQC: protein quality control; PxxP: proline-rich; RAN translation: repeat-associated non-AUG translation; SG: stress granule; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; STK: serine/threonine kinase; SYNPO: synaptopodin; TBP: TATA-box binding protein; TARDBP/TDP-43: TAR DNA binding protein; TFEB: transcription factor EB; TPR: tetratricopeptide repeats; TSC1: TSC complex subunit 1; UBA: ubiquitin associated; UPS: ubiquitin-proteasome system; WW: tryptophan-tryptophan; WWTR1: WW domain containing transcription regulator 1; YAP1: Yes1 associated transcriptional regulator.
    Keywords:  Aggresome; BAG3; HSPA; HSPB8; SQSTM1; STUB1; misfolding; myopathy; neurodegenerative diseases; neuropathy; proteostasis
    DOI:  https://doi.org/10.1080/15548627.2022.2160564
  2. Front Mol Neurosci. 2022 ;15 1050472
    The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation.
    Adam S Knier, Emily E Davis, Hannah E Buchholz, Jane E Dorweiler, Lauryn E Flannagan, Anita L Manogaran.
      Patients with the fatal disorder Transthyretin Amyloidosis (ATTR) experience polyneuropathy through the progressive destruction of peripheral nervous tissue. In these patients, the transthyretin (TTR) protein dissociates from its functional tetrameric structure, misfolds, and aggregates into extracellular amyloid deposits that are associated with disease progression. These aggregates form large fibrillar structures as well as shorter oligomeric aggregates that are suspected to be cytotoxic. Several studies have shown that these extracellular TTR aggregates enter the cell and accumulate intracellularly, which is associated with increased proteostasis response. However, there are limited experimental models to study how proteostasis influences internalized TTR aggregates. Here, we use a humanized yeast system to recapitulate intracellular TTR aggregating protein in vivo. The yeast molecular chaperone Hsp104 is a disaggregase that has been shown to fragment amyloidogenic aggregates associated with certain yeast prions and reduce protein aggregation associated with human neurogenerative diseases. In yeast, we found that TTR forms both SDS-resistant oligomers and SDS-sensitive large molecular weight complexes. In actively dividing cultures, Hsp104 has no impact on oligomeric or large aggregate populations, yet overexpression of Hsp104 is loosely associated with an increase in overall aggregate size. Interestingly, a potentiating mutation in the middle domain of Hsp104 consistently results in an increase in overall TTR aggregate size. These data suggest a novel approach to aggregate management, where the Hsp104 variant shifts aggregate populations away from toxic oligomeric species to more inert larger aggregates. In aged cultures Hsp104 overexpression has no impact on TTR aggregation profiles suggesting that these chaperone approaches to shift aggregate populations are not effective with age, possibly due to proteostasis decline.
    Keywords:  Hsp104; aging; amyloid; molecular chaperone; polyneuropathy; protein aggregation; transthyretin; transthyretin amyloidosis
    DOI:  https://doi.org/10.3389/fnmol.2022.1050472
  3. Subcell Biochem. 2023 ;102 99-112
    The Proteasome and Ageing.
    Ashok N Hegde, Lindsey M Duke, Logan E Timm, Hannah Nobles.
      The proteasome is a multi-subunit proteolytic complex that functions to degrade normal proteins for physiological regulation and to eliminate abnormal proteins for cellular protection. Generally, the proteasome targets substrate proteins that are marked by attachment of multiple ubiquitin molecules. In various types of cells in an organism, damage to proteins occurs both from internal sources such as reactive oxygen species and from external ones such as UV radiation from the sun. The proteasome functions to protect the cells by degrading damaged proteins. With ageing, however, the capacity of the proteasome to degrade damaged proteins is reduced as indicated by evidence gathered by many studies. Studies on ageing in muscle, skin, and brain show that with age catalytic activity of the proteasome is decreased and the expression of proteasome subunits is altered. Age-related accumulation of damaged or misfolded proteins causes further reduction of proteasome activity. Abnormal proteins also accumulate as a result of age-related neurodegenerative diseases. Deficits in proteasome activity might be responsible for accumulation of protein aggregates and thus contribute to the pathology. Results from several studies suggest a link between the proteasome and longevity. This chapter reviews the various ways in which the proteasome is associated with the ageing process and examines evidence gathered from investigations on cultured cells, model organisms, and humans.
    Keywords:  Longevity; Misfolded proteins; Neurodegeneration; Oxidative damage; Protein degradation; Proteolysis; Proteostasis; Senescence; Ubiquitin
    DOI:  https://doi.org/10.1007/978-3-031-21410-3_5
  4. Cell. 2022 Dec 26. pii: S0092-8674(22)01377-0. [Epub ahead of print]
    Hallmarks of aging: An expanding universe.
    Carlos López-Otín, Maria A Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer.
      Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
    DOI:  https://doi.org/10.1016/j.cell.2022.11.001
  5. Theranostics. 2023 ;13(1): 197-230
    Role of primary aging hallmarks in Alzheimer´s disease.
    Jin Zhao, Jisen Huai.
      Alzheimer's disease (AD) is the most common neurodegenerative disease, which severely threatens the health of the elderly and causes significant economic and social burdens. The causes of AD are complex and include heritable but mostly aging-related factors. The primary aging hallmarks include genomic instability, telomere wear, epigenetic changes, and loss of protein stability, which play a dominant role in the aging process. Although AD is closely associated with the aging process, the underlying mechanisms involved in AD pathogenesis have not been well characterized. This review summarizes the available literature about primary aging hallmarks and their roles in AD pathogenesis. By analyzing published literature, we attempted to uncover the possible mechanisms of aberrant epigenetic markers with related enzymes, transcription factors, and loss of proteostasis in AD. In particular, the importance of oxidative stress-induced DNA methylation and DNA methylation-directed histone modifications and proteostasis are highlighted. A molecular network of gene regulatory elements that undergoes a dynamic change with age may underlie age-dependent AD pathogenesis, and can be used as a new drug target to treat AD.
    Keywords:  Aging; Alzheimer's disease; Epigenetics; Molecular neurobiology; Neurodegeneration; Oxidative stress
    DOI:  https://doi.org/10.7150/thno.79535
  6. Front Mol Biosci. 2022 ;9 1045616
    The role of heat shock proteins in preventing amyloid toxicity.
    Ricarda Törner, Tatsiana Kupreichyk, Wolfgang Hoyer, Jerome Boisbouvier.
      The oligomerization of monomeric proteins into large, elongated, β-sheet-rich fibril structures (amyloid), which results in toxicity to impacted cells, is highly correlated to increased age. The concomitant decrease of the quality control system, composed of chaperones, ubiquitin-proteasome system and autophagy-lysosomal pathway, has been shown to play an important role in disease development. In the last years an increasing number of studies has been published which focus on chaperones, modulators of protein conformational states, and their effects on preventing amyloid toxicity. Here, we give a comprehensive overview of the current understanding of chaperones and amyloidogenic proteins and summarize the advances made in elucidating the impact of these two classes of proteins on each other, whilst also highlighting challenges and remaining open questions. The focus of this review is on structural and mechanistic studies and its aim is to bring novices of this field "up to speed" by providing insight into all the relevant processes and presenting seminal structural and functional investigations.
    Keywords:  HSP; aggregation; amyloid; chaperones; structural biology
    DOI:  https://doi.org/10.3389/fmolb.2022.1045616
  7. Neuroscientist. 2023 Jan 03. 10738584221139761
    Mitochondria in Aging and Alzheimer's Disease: Focus on Mitophagy.
    Jangampalli Adi Pradeepkiran, Javaria Baig, Ashley Selman, P Hemachandra Reddy.
      Alzheimer's disease (AD) is characterized by the accumulation of amyloid β and phosphorylated τ protein aggregates in the brain, which leads to the loss of neurons. Under the microscope, the function of mitochondria is uniquely primed to play a pivotal role in neuronal cell survival, energy metabolism, and cell death. Research studies indicate that mitochondrial dysfunction, excessive oxidative damage, and defective mitophagy in neurons are early indicators of AD. This review article summarizes the latest development of mitochondria in AD: 1) disease mechanism pathways, 2) the importance of mitochondria in neuronal functions, 3) metabolic pathways and functions, 4) the link between mitochondrial dysfunction and mitophagy mechanisms in AD, and 5) the development of potential mitochondrial-targeted therapeutics and interventions to treat patients with AD.
    Keywords:  Alzheimer disease; adenosine triphosphate; amyloid beta; amyloid precursor protein; dysfunction; mitochondria; mitophagy; neurofibrillary tangle; p-tau; reaction oxidative stress; therapeutics
    DOI:  https://doi.org/10.1177/10738584221139761
  8. Front Endocrinol (Lausanne). 2022 ;13 1085522
    Autophagy and longevity: Evolutionary hints from hyper-longevous mammals.
    Andrea G Locatelli, Simone Cenci.
      Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging.
    Keywords:   aging; ATG; age-related diseases; autophagy; bats; evolution; longevity; mitochondria
    DOI:  https://doi.org/10.3389/fendo.2022.1085522
  9. Cell Rep. 2022 Dec 23. pii: S2211-1247(22)01795-8. [Epub ahead of print] 111896
    Efficient generation of lower induced motor neurons by coupling Ngn2 expression with developmental cues.
    Francesco Limone, Irune Guerra San Juan, Jana M Mitchell, Janell L M Smith, Kavya Raghunathan, Daniel Meyer, Sulagna Dia Ghosh, Alexander Couto, Joseph R Klim, Brian J Joseph, John Gold, Curtis J Mello, James Nemesh, Brittany M Smith, Matthijs Verhage, Steven A McCarroll, Olli Pietiläinen, Ralda Nehme, Kevin Eggan.
      Human pluripotent stem cells (hPSCs) are a powerful tool for disease modeling of hard-to-access tissues (such as the brain). Current protocols either direct neuronal differentiation with small molecules or use transcription-factor-mediated programming. In this study, we couple overexpression of transcription factor Neurogenin2 (Ngn2) with small molecule patterning to differentiate hPSCs into lower induced motor neurons (liMoNes/liMNs). This approach induces canonical MN markers including MN-specific Hb9/MNX1 in more than 95% of cells. liMNs resemble bona fide hPSC-derived MN, exhibit spontaneous electrical activity, express synaptic markers, and can contact muscle cells in vitro. Pooled, multiplexed single-cell RNA sequencing on 50 hPSC lines reveals reproducible populations of distinct subtypes of cervical and brachial MNs that resemble their in vivo, embryonic counterparts. Combining small molecule patterning with Ngn2 overexpression facilitates high-yield, reproducible production of disease-relevant MN subtypes, which is fundamental in propelling our knowledge of MN biology and its disruption in disease.
    Keywords:  CP: Neuroscience; CP: Stem cell research; Dropulation; NGN2; differentiation protocol; human stem cells; motor neuron; multiplexed pooled sequencing; neuronal differentiation; patterning molecules; single cell profiling; spinal cord
    DOI:  https://doi.org/10.1016/j.celrep.2022.111896
  10. Subcell Biochem. 2023 ;102 365-377
    Ageing Skeletal Muscle: The Ubiquitous Muscle Stem Cell.
    Claire E Stewart.
      In 1999, in a review by Beardsley, the potential of adult stem cells, in repair and regeneration was heralded (Beardsley Sci Am 281:30-31, 1999). Since then, the field of regenerative medicine has grown exponentially, with the capability of restoring or regenerating the function of damaged, diseased or aged human tissues being an underpinning motivation. If successful, stem cell therapies offer the potential to treat, for example degenerative diseases. In the subsequent 20 years, extensive progress has been made in the arena of adult stem cells (for a recent review see (Zakrzewski et al. Stem Cell Res Ther 10:68, 2019)). Prior to the growth of the adult stem cell research arena, much focus had been placed on the potential of embryonic stem cells (ESCs). The first research revealing the potential of these cells was published in 1981, when scientists reported the ability of cultured stem cells from murine embryos, to not only self-renew, but to also become all cells of the three germ layers of the developing embryo (Evans and Kaufman Nature 292:154-156, 1981), (Martin Proc Natl Acad Sci U S A 78:7634-7638, 1981). It took almost 20 years, following these discoveries, for this technology to translate to human ESCs, using donated human embryos. In 1998, Thomson et al. reported the creation of the first human embryonic cell line (Thomson et al. Science 282:1145-1147, 1998). However, research utilising human ESCs was hampered by ethical and religious constraints and indeed in 2001 George W. Bush restricted US research funding to human ESCs, which had already been banked. The contentious nature of this arena perhaps facilitated the use of and the research potential for adult stem cells. It is beyond the scope of this review to focus on ESCs, although their potential for enhancing our understanding of human development is huge (for a recent review see (Cyranoski Nature 555:428-430, 2018)). Rather, although ESCs and their epigenetic regulation will be introduced for background understanding, the focus will be on stem cells more generally, the role of epigenetics in stem cell fate, skeletal muscle, skeletal muscle stem cells, the impact of ageing on muscle wasting and the mechanisms underpinning loss, with a focus on epigenetic adaptation.
    Keywords:  Ageing; Epigenetics; Muscle; Myoblast; Sarcopenia; Stem cell
    DOI:  https://doi.org/10.1007/978-3-031-21410-3_14
  11. Surg Neurol Int. 2022 ;13 595
    Could an old brain be made young again?
    Jean M Hébert.
      
    DOI:  https://doi.org/10.25259/SNI_1132_2022
  12. Mol Biol Cell. 2023 Jan 04. mbcE22040137
    Differentiation-dependent changes in Lamin B1 dynamics and Lamin B Receptor localization.
    Chase C Wesley, Daniel L Levy.
      The nuclear lamina serves important roles in chromatin organization and structural support, and lamina mutations can result in laminopathies. Less is known about how nuclear lamina structure changes during cellular differentiation, changes that may influence gene regulation. We examined the structure and dynamics of the nuclear lamina in human induced pluripotent stem cells (iPSCs) and differentiated germ layer cells, focusing on Lamin B1. We report that Lamin B1 dynamics generally increase as iPSCs differentiate, especially in mesoderm and ectoderm, and that Lamin B Receptor (LBR) partially redistributes from the nucleus to cytoplasm in mesoderm. Knocking down LBR in iPSCs led to an increase in Lamin B1 dynamics, a change that was not observed for ELYS, emerin, or Lamin B2 knockdown. LBR knockdown also affected expression of differentiation markers. These data suggest that differentiation-dependent tethering of Lamin B1 either directly by LBR or indirectly via LBR-chromatin associations impacts gene expression.
    DOI:  https://doi.org/10.1091/mbc.E22-04-0137
  13. J Neuroinflammation. 2023 Jan 03. 20(1): 3
    Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function.
    Evangelos Konstantinidis, Benjamin Portal, Tobias Mothes, Chiara Beretta, Maria Lindskog, Anna Erlandsson.
       BACKGROUND: Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous data demonstrate that astrocytes ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade the ingested material, which leads to severe cellular stress. However, the involvement of pathological astrocytes in AD-related synaptic dysfunction remains to be elucidated.
    METHODS: In this study, we aimed to investigate how intracellular deposits of Aβ in astrocytes affect their interplay with neurons, focusing on neuronal function and viability. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils. The direct and indirect effects of the Αβ-exposed astrocytes on hiPSC-derived neurons were analyzed by performing astrocyte-neuron co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.
    RESULTS: Electrophysiological recordings revealed significantly decreased frequency of excitatory post-synaptic currents in neurons co-cultured with Aβ-exposed astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect and resulted in hyperactivation of the synapses. Clearly, factors secreted from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal cultures. Moreover, reactive astrocytes with Aβ deposits led to an elevated clearance of dead cells in the co-cultures.
    CONCLUSIONS: Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactive state of the astrocytes, as well as their ability to support neuronal function.
    Keywords:  Alzheimer’s disease; Amyloid-beta; Astrocytes; EPSCs; Electrophysiology; Neurons; iPSCs
    DOI:  https://doi.org/10.1186/s12974-022-02687-5
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