bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023‒03‒12
eight papers selected by
Rich Giadone
Harvard University
  1. Regulation of germline proteostasis by HSF1 and insulin/IGF-1 signaling.
  2. Protein homeostasis in aging and cancer.
  3. Role of conformational dynamics in pathogenic protein aggregation.
  4. Comprehensive perspective towards the management of proteinopathies by elucidating protein misfolding and aggregation.
  5. Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.
  6. Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals.
  7. Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.
  8. Ribosome biogenesis and function in development and disease.
  1. Biochem Soc Trans. 2023 Mar 09. pii: BST20220616. [Epub ahead of print]
    Regulation of germline proteostasis by HSF1 and insulin/IGF-1 signaling.
    Tahir Muhammad, Jian Li.
      Protein homeostasis (proteostasis) is essential for cellular function and organismal health and requires the concerted actions of protein synthesis, folding, transport, and turnover. In sexually reproducing organisms, the immortal germline lineage passes genetic information across generations. Accumulating evidence indicates the importance of proteome integrity for germ cells as genome stability. As gametogenesis involves very active protein synthesis and is highly energy-demanding, it has unique requirements for proteostasis regulation and is sensitive to stress and nutrient availability. The heat shock factor 1 (HSF1), a key transcriptional regulator of cellular response to cytosolic and nuclear protein misfolding has evolutionarily conserved roles in germline development. Similarly, insulin/insulin-like growth factor-1 (IGF-1) signaling, a major nutrient-sensing pathway, impacts many aspects of gametogenesis. Here, we focus on HSF1 and IIS to review insights into their roles in germline proteostasis and discuss the implications on gamete quality control during stress and aging.
    Keywords:  HSF1; gametogenesis; insulin/IGF-1 signaling; proteostasis; stress response
    DOI:  https://doi.org/10.1042/BST20220616
  2. Front Cell Dev Biol. 2023 ;11 1143532
    Protein homeostasis in aging and cancer.
    Xiao-Qiong Chen, Tao Shen, Shao-Jun Fang, Xiao-Min Sun, Guo-Yu Li, Yun-Feng Li.
      Aging is a major risk factor for cancer development. As dysfunction in protein homeostasis, or proteostasis, is a universal hallmark of both the aging process and cancer, a comprehensive understanding of the proteostasis system and its roles in aging and cancer will shed new light on how we can improve health and quality of life for older individuals. In this review, we summarize the regulatory mechanisms of proteostasis and discuss the relationship between proteostasis and aging and age-related diseases, including cancer. Furthermore, we highlight the clinical application value of proteostasis maintenance in delaying the aging process and promoting long-term health.
    Keywords:  aging; autophagy-lysosomal system; cancer; molecular chaperones; protein homeostasis; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3389/fcell.2023.1143532
  3. Curr Opin Chem Biol. 2023 Mar 04. pii: S1367-5931(23)00018-2. [Epub ahead of print]73 102280
    Role of conformational dynamics in pathogenic protein aggregation.
    Xun Sun, H Jane Dyson, Peter E Wright.
      The accumulation of pathogenic protein oligomers and aggregates is associated with several devastating amyloid diseases. As protein aggregation is a multi-step nucleation-dependent process beginning with unfolding or misfolding of the native state, it is important to understand how innate protein dynamics influence aggregation propensity. Kinetic intermediates composed of heterogeneous ensembles of oligomers are frequently formed on the aggregation pathway. Characterization of the structure and dynamics of these intermediates is critical to the understanding of amyloid diseases since oligomers appear to be the main cytotoxic agents. In this review, we highlight recent biophysical studies of the roles of protein dynamics in driving pathogenic protein aggregation, yielding new mechanistic insights that can be leveraged for design of aggregation inhibitors.
    Keywords:  Abeta; Alpha-synuclein; Amyloid disease; Aβ; Biophysical characterization; Huntingtin; Oligomeric intermediates; Transthyretin; α-synuclein
    DOI:  https://doi.org/10.1016/j.cbpa.2023.102280
  4. CNS Neurol Disord Drug Targets. 2023 Mar 06.
    Comprehensive perspective towards the management of proteinopathies by elucidating protein misfolding and aggregation.
    Ishfaq Ahmad Ahanger, Ghulam Md Ashraf, Anurag Sharma, Asimul Islam.
      Protein misfolding and aggregation is the phenomenon of the generic propensity of proteins, considered as a dark side of the protein world, and its exact mechanism is still not deciphered. Understanding the complexity of protein aggregation is currently the primary apprehension and challenge in biology and medicine due to their association with various debilitating human proteinopathies and neurodegenerative diseases. The mechanism of protein aggregation, associated diseases, and the development of efficient therapeutic strategies against these diseases are very challenging. These diseases are caused by different proteins, each protein with different mechanisms and consisting of various microscopic phases or events. These microscopic steps are functioning on different timescales during aggregation. Here, we highlighted the different features and current trends in protein aggregation. The study thoroughly recapitulates the various factors influencing, possible causes, types of aggregates and aggregation, their different proposed mechanisms, and the methods used to study the aggregation. Additionally, the formation and elimination of misfolded or aggregated proteins in the cell, the role of the ruggedness of the protein folding landscape in protein aggregation, proteinopathies, and the challenges for their prevention are comprehensively elucidated. A holistic understanding of different aspects of aggregation, molecular steps governing the various features of protein quality control, and crucial queries about the modulation of these processes and their interactions with other systems in cellular protein quality control can be considered conducive to comprehending the mechanism, designing effective approaches towards prevention of protein aggregation, rationalizing the etiology and development of novel strategies against therapy and management of the proteinopathies.
    Keywords:  Protein aggregation; generic propensity; neurodegenerative diseases; protein folding landscape; protein quality control.; proteinopathies
    DOI:  https://doi.org/10.2174/1871527322666230306085937
  5. Front Aging Neurosci. 2023 ;15 1047897
    Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.
    Yu-Mi Jeon, Younghwi Kwon, Shinrye Lee, Hyung-Jun Kim.
      The endoplasmic reticulum (ER) is a major organelle involved in protein quality control and cellular homeostasis. ER stress results from structural and functional dysfunction of the organelle, along with the accumulation of misfolded proteins and changes in calcium homeostasis, it leads to ER stress response pathway such as unfolded protein response (UPR). Neurons are particularly sensitive to the accumulation of misfolded proteins. Thus, the ER stress is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion disease and motor neuron disease (MND). Recently, the complex involvement of ER stress pathways has been demonstrated in experimental models of amyotrophic lateral sclerosis (ALS)/MND using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive response to ER stress. Here, we aim to provide recent evidence demonstrating that the ER stress pathway is an essential pathological mechanism of ALS. In addition, we also provide therapeutic strategies that can help treat diseases by targeting the ER stress pathway.
    Keywords:  amyotrophic lateral sclerosis; endoplasmic reticulum stress; motor neuron disease; therapeutic target; unfolded protein response
    DOI:  https://doi.org/10.3389/fnagi.2023.1047897
  6. Cells. 2023 Feb 27. pii: 758. [Epub ahead of print]12(5):
    Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals.
    Giulia Cencelli, Laura Pacini, Anastasia De Luca, Ilenia Messia, Antonietta Gentile, Yunhee Kang, Veronica Nobile, Elisabetta Tabolacci, Peng Jin, Maria Giulia Farace, Claudia Bagni.
      Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.
    Keywords:  ADAM10; APP processing; Fragile X syndrome; SAP97; iPSCs; peptide therapy; protein synthesis
    DOI:  https://doi.org/10.3390/cells12050758
  7. Commun Biol. 2023 Mar 09. 6(1): 252
    Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.
    Zhuoran Wang, Qiang Li, Brad J Kolls, Brian Mace, Shu Yu, Xuan Li, Wei Liu, Eduardo Chaparro, Yuntian Shen, Lihong Dang, Ángela Del Águila, Joshua D Bernstock, Kory R Johnson, Junjie Yao, William C Wetsel, Scott D Moore, Dennis A Turner, Wei Yang.
      The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABAA receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.
    DOI:  https://doi.org/10.1038/s42003-023-04594-8
  8. Development. 2023 Mar 01. pii: dev201187. [Epub ahead of print]150(5):
    Ribosome biogenesis and function in development and disease.
    Chunyang Ni, Michael Buszczak.
      Although differential transcription drives the development of multicellular organisms, the ultimate readout of a protein-coding gene is ribosome-dependent mRNA translation. Ribosomes were once thought of as uniform molecular machines, but emerging evidence indicates that the complexity and diversity of ribosome biogenesis and function should be given a fresh look in the context of development. This Review begins with a discussion of different developmental disorders that have been linked with perturbations in ribosome production and function. We then highlight recent studies that reveal how different cells and tissues exhibit variable levels of ribosome production and protein synthesis, and how changes in protein synthesis capacity can influence specific cell fate decisions. We finish by touching upon ribosome heterogeneity in stress responses and development. These discussions highlight the importance of considering both ribosome levels and functional specialization in the context of development and disease.
    Keywords:  Biogenesis; Differentiation; Heterogeneity; Ribosome; Ribosome concentration; Ribosome specialization; Stem cells; mRNA translation
    DOI:  https://doi.org/10.1242/dev.201187
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