bims-proarb 2023-02-26 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2023–02–26
nine papers selected by
Rich Giadone, Harvard University

Organismal Roles of Hsp90.
Extracellular protein homeostasis in neurodegenerative diseases.
Hallmarks of neurodegenerative diseases.
Editorial: Protein homeostasis in growth, development and disease.
Protein Misfolding and Aggregation in Proteinopathies: Causes, Mechanism and Cellular Response.
Obesity impacts placental function through activation of p-IRE1a-XBP1s signaling.
Editorial: Protein misfolding, altered mechanisms and neurodegeneration.
Oligodendrocyte Progenitors Display Enhanced Proliferation and Autophagy after Space Flight.
Early postnatal defects in neurogenesis in the 3xTg mouse model of Alzheimer's disease.

Biomolecules. 2023 Jan 29. pii: 251. [Epub ahead of print]13(2):

Organismal Roles of Hsp90.

Patricija van Oosten-Hawle.

  Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals.

Keywords:  Hsp90; cell nonautonomous; inter-tissue stress signaling; organismal; proteostasis; stress response

DOI:  https://doi.org/10.3390/biom13020251
Nat Rev Neurol. 2023 Feb 24.

Extracellular protein homeostasis in neurodegenerative diseases.

Mark R Wilson, Sandeep Satapathy, Michele Vendruscolo.

The protein homeostasis (proteostasis) system encompasses the cellular processes that regulate protein synthesis, folding, concentration, trafficking and degradation. In the case of intracellular proteostasis, the identity and nature of these processes have been extensively studied and are relatively well known. By contrast, the mechanisms of extracellular proteostasis are yet to be fully elucidated, although evidence is accumulating that their age-related progressive impairment might contribute to neuronal death in neurodegenerative diseases. Constitutively secreted extracellular chaperones are emerging as key players in processes that operate to protect neurons and other brain cells by neutralizing the toxicity of extracellular protein aggregates and promoting their safe clearance and disposal. Growing evidence indicates that these extracellular chaperones exert multiple effects to promote cell viability and protect neurons against pathologies arising from the misfolding and aggregation of proteins in the synaptic space and interstitial fluid. In this Review, we outline the current knowledge of the mechanisms of extracellular proteostasis linked to neurodegenerative diseases, and we examine the latest understanding of key molecules and processes that protect the brain from the pathological consequences of extracellular protein aggregation and proteotoxicity. Finally, we contemplate possible therapeutic opportunities for neurodegenerative diseases on the basis of this emerging knowledge.

DOI: https://doi.org/10.1038/s41582-023-00786-2
Cell. 2023 Feb 16. pii: S0092-8674(22)01575-6. [Epub ahead of print]186(4): 693-714

Hallmarks of neurodegenerative diseases.

David M Wilson, Mark R Cookson, Ludo Van Den Bosch, Henrik Zetterberg, David M Holtzman, Ilse Dewachter.

  Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.

Keywords:  DNA and RNA defects; cytoskeletal defects; energy homeostasis; hallmarks; inflammation; neurodegeneration; neurodegenerative disease; protein aggregation; proteostasis; synaptic and neuronal network dysfunction

DOI:  https://doi.org/10.1016/j.cell.2022.12.032
Front Cell Dev Biol. 2023 ;11 1150158

Editorial: Protein homeostasis in growth, development and disease.

Silvia Masciarelli, Francesco Fazi, Linda M Hendershot.



Keywords:  homeostasis and differentiation; molecular chaperones and chaperonins; proteostasis; quality control in the endoplasmic reticulum; stress responses

DOI:  https://doi.org/10.3389/fcell.2023.1150158
Diseases. 2023 Feb 09. pii: 30. [Epub ahead of print]11(1):

Protein Misfolding and Aggregation in Proteinopathies: Causes, Mechanism and Cellular Response.

Mohammad Rehan Ajmal.

  Proteins are central to life functions. Alterations in the structure of proteins are reflected in their function. Misfolded proteins and their aggregates present a significant risk to the cell. Cells have a diverse but integrated network of protection mechanisms. Streams of misfolded proteins that cells are continuously exposed to must be continually monitored by an elaborated network of molecular chaperones and protein degradation factors to control and contain protein misfolding problems. Aggregation inhibition properties of small molecules such as polyphenols are important as they possess other beneficial properties such as antioxidative, anti-inflammatory, and pro-autophagic properties and help neuroprotection. A candidate with such desired features is important for any possible treatment development for protein aggregation diseases. There is a need to study the protein misfolding phenomenon so that we can treat some of the worst kinds of human ailments related to protein misfolding and aggregation.

Keywords:  aggregation inhibition; amyloid diseases; inflammation; neurodegeneration; protein aggregation

DOI:  https://doi.org/10.3390/diseases11010030
Front Cell Dev Biol. 2023 ;11 1023327

Obesity impacts placental function through activation of p-IRE1a-XBP1s signaling.

Wei-Bin Shen, Bingbing Wang, Ruofan Yao, Katherine R Goetzinger, Sheng Wu, Haijun Gao, Peixin Yang.

  Maternal obesity is associated with a variety of obstetrical outcomes including stillbirth, preeclampsia, and gestational diabetes, and increases the risk of fetuses for congenital heart defects. Obesity during pregnancy represents a major contribution to metabolic dysregulation, which not only plays a key role in the pathogenesis of adverse outcome but also can potently induce endoplasmic reticulum (ER) stress. However, the mechanism associating such an obesogenic metabolic environment and adverse pregnancy outcomes has remained poorly understood. In this study, we aimed to determine whether the ER stress pathways (also named unfolded protein response (UPR)) were activated in the placenta by obesity. We collected placenta from the obese pregnancy (n = 12) and non-obese pregnancy (n = 12) following delivery by Caesarean-section at term. The specimens were assessed with immunocytochemistry staining and RT-QPCR. Our results revealed that in the obese placenta, p-IRE1α and XBP1s were significantly increased, CHOP and nine UPR chaperone genes were upregulated, including GRP95, PDIA6, Calnexin, p58IPK, SIL-1, EDEM, Herp, GRP58 and Calreticulin. However, Perk and BiP are not activated in the obese placenta. Our data suggest that upregulated p-IRE1α and XBP1s signaling, and UPR chaperone genes may play an important role in maternal obesity-induced placental pathology. In conclusion, this is the first report on ER stress and UPR activation in the placenta of maternal obesity. Our findings represent the first step in the understanding of one of the key ER signaling pathways, also referred to IRE1α-XBP1, in placental pathophysiology affected by obesity, which may be an important mechanism accounting for the observed higher maternal and perinatal risks.

Keywords:  IRE1α; XBP1S; chaperones; endoplasmic reticulum stress; maternal obese; placenta

DOI:  https://doi.org/10.3389/fcell.2023.1023327
Front Mol Neurosci. 2023 ;16 1134855

Editorial: Protein misfolding, altered mechanisms and neurodegeneration.

Neha Gogia, Meghana Tare, Ramakrishnan Kannan, Amit Singh.



Keywords:  Drosophila; Protein misfolding; animal models; disease mechanisms; human neurodegenerative diseases; neurodegeneration; proteinopathies; therapeutics

DOI:  https://doi.org/10.3389/fnmol.2023.1134855
Biomolecules. 2023 Jan 19. pii: 201. [Epub ahead of print]13(2):

Oligodendrocyte Progenitors Display Enhanced Proliferation and Autophagy after Space Flight.

Victoria Tran, Nicholas Carpo, Carlos Cepeda, Araceli Espinosa-Jeffrey.

  Intracranial hypertension (ICP) and visual impairment intracranial pressure (VIIP) are some of the consequences of long-term space missions. Here we examined the behavior of oligodendrocyte progenitors (OLPs) after space flight using time-lapse microscopy. We show that most OLPs divided more than ground control (GC) counterparts did. Nonetheless, a subpopulation of OLPs flown to space presented a significant increase in autophagic cell death. Examination of the proteomic profile of the secretome of space flown OLPs (SPC-OLPs) revealed that the stress protein heat shock protein-90 beta "HSP-90β" was the 5th most enriched (6.8 times) and the secreted protein acidic and rich in cysteine "SPARC" was the 7th most enriched (5.2 times), with respect to ground control cells. SPARC induces endoplasmic reticulum stress, which leads to autophagy. Given the roles and importance of these two proteins in mammalian cells' metabolism, their upregulation may hold the key to modulating cell proliferation and autophagy, in order to mitigate ICP and VIIP during and after space missions.

Keywords:  HSP-90; SPARC; autophagy; intracranial hypertension; oligodendrocyte progenitors; proliferation; space flight; visual impairment intracranial pressure

DOI:  https://doi.org/10.3390/biom13020201
Cell Death Dis. 2023 Feb 18. 14(2): 138

Early postnatal defects in neurogenesis in the 3xTg mouse model of Alzheimer's disease.

Yubing Liu, Maria Bilen, Marie-Michelle McNicoll, Richard A Harris, Bensun C Fong, Mohamed Ariff Iqbal, Smitha Paul, Janice Mayne, Krystal Walker, Jing Wang, Daniel Figeys, Ruth S Slack.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to dementia. The hippocampus, which is one of the sites where neural stem cells reside and new neurons are born, exhibits the most significant neuronal loss in AD. A decline in adult neurogenesis has been described in several animal models of AD. However, the age at which this defect first appears remains unknown. To determine at which stage, from birth to adulthood, the neurogenic deficits are found in AD, we used the triple transgenic mouse model of AD (3xTg). We show that defects in neurogenesis are present as early as postnatal stages, well before the onset of any neuropathology or behavioral deficits. We also show that 3xTg mice have significantly fewer neural stem/progenitor cells, with reduced proliferation and decreased numbers of newborn neurons at postnatal stages, consistent with reduced volumes of hippocampal structures. To determine whether there are early changes in the molecular signatures of neural stem/progenitor cells, we perform bulk RNA-seq on cells sorted directly from the hippocampus. We show significant changes in the gene expression profiles at one month of age, including genes of the Notch and Wnt pathways. These findings reveal impairments in neurogenesis very early in the 3xTg AD model, which provides new opportunities for early diagnosis and therapeutic interventions to prevent neurodegeneration in AD.

DOI: https://doi.org/10.1038/s41419-023-05650-1