bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2023–07–30
six papers selected by
Verena Kohler, University of Graz
  1. Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases.
  2. Amyloid β accelerates age-related proteome-wide protein insolubility.
  3. Lysophospholipids transport across blood-brain barrier in an in vitro reconstruction model.
  4. UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.
  5. The Effects of Serping1 siRNA in α-Synuclein Regulation in MPTP-Induced Parkinson's Disease.
  6. Lipid-induced polymorphic amyloid fibril formation by α-synuclein.
  1. Int J Mol Sci. 2023 Jul 10. pii: 11275. [Epub ahead of print]24(14):
    Targeting Protein Aggregates with Natural Products: An Optional Strategy for Neurodegenerative Diseases.
    Lingzhi Xiang, Yanan Wang, Shenkui Liu, Beidong Liu, Xuejiao Jin, Xiuling Cao.
      Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.
    Keywords:  Aβ; FUS; Htt; natural products; neurodegenerative diseases; protein aggregation; tau; α-Syn
    DOI:  https://doi.org/10.3390/ijms241411275
  2. bioRxiv. 2023 Jul 16. pii: 2023.07.13.548937. [Epub ahead of print]
    Amyloid β accelerates age-related proteome-wide protein insolubility.
    Edward Anderton, Manish Chamoli, Dipa Bhaumik, Christina D King, Xueshu Xie, Anna Foulger, Julie K Andersen, Birgit Schilling, Gordon J Lithgow.
      Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases including Alzheimer's Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the established connection between aging and AD risk, therapeutic approaches to date have overlooked aging and proteome-wide protein insolubility as causal factors, instead focusing on Aβ and Tau. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. We demonstrate that, in C. elegans , Aβ expression is sufficient to drive proteome-wide protein insolubility. The Aβ-driven insoluble proteome bears a highly significant overlap with the aging-driven insoluble proteome, suggesting there exists a core, sub-proteome which is vulnerable to insolubility. Using human genome-wide association studies (GWAS) we show that this insoluble sub proteome is replete with biological processes implicated across not only neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs), providing suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the gut metabolite, Urolithin A, relieves Aβ toxicity supporting its use in clinical trials for dementia and other age-related diseases.
    DOI:  https://doi.org/10.1101/2023.07.13.548937
  3. Biochem Biophys Res Commun. 2023 Jul 22. pii: S0006-291X(23)00910-5. [Epub ahead of print]676 91-96
    Lysophospholipids transport across blood-brain barrier in an in vitro reconstruction model.
    Tamotsu Tsukahara, Masanori Sasaki, Hisao Haniu, Yoshikazu Matsuda.
      This study builds on our previous study, which highlighted the need for further research on the potential use of lysophospholipid (LPL) supplementation to prevent chronic and age-related diseases. We aimed to evaluate the transmembrane transport of LPL across rat and monkey blood-brain barrier (BBB) models. An in vitro monkey BBB model is required to elucidate the differences between rat and primate BBB-related data and to measure the permeability of LPLs being researched in relation to the human BBB. Based on our previous experiment, porcine liver decomposition product-derived phospholipids (PEL) strongly inhibit α-synuclein (α-Syn) aggregation. We have identified several candidates potentially relevant for the inhibition of α-Syn aggregation, such as LPC18:1, LPE18:1, and LPI18:0; however, the BBB permeability of these LPLs remains unclear. In the present study, we assessed the ability of these LPLs to pass through the in vitro rat and monkey BBB models. LPC18:1 showed high BBB permeability, LPI18:0 showed medium permeability, and the BBB permeation of LPE18:1 was negligible. Our results suggest that LPC18:1 and LPI18:0 are functional food factors that can cross the BBB.
    Keywords:  Blood-brain barrier; Lysophospholipid; Transmembrane transport; α-Syn aggregation
    DOI:  https://doi.org/10.1016/j.bbrc.2023.07.044
  4. EMBO Rep. 2023 Jul 28. e55859
    UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture.
    Qilian Ma, Jiaqi Xin, Qiang Peng, Ningning Li, Shan Sun, Hongyu Hou, Guoqiang Ma, Nana Wang, Li Zhang, Kin Yip Tam, Heiko Dussmann, Jochen Hm Prehn, Hongfeng Wang, Zheng Ying.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two aging-related neurodegenerative diseases that share common key features, including aggregation of pathogenic proteins, dysfunction of mitochondria, and impairment of autophagy. Mutations in ubiquilin 2 (UBQLN2), a shuttle protein in the ubiquitin-proteasome system (UPS), can cause ALS/FTD, but the mechanism underlying UBQLN2-mediated pathogenesis is still uncertain. Recent studies indicate that mitophagy, a selective form of autophagy which is crucial for mitochondrial quality control, is tightly associated with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and ALS. In this study, we show that after Parkin-dependent ubiquitination of damaged mitochondria, UBQLN2 is recruited to poly-ubiquitinated mitochondria through the UBA domain. UBQLN2 cooperates with the chaperone HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins. The resulting rupture of the OMM triggers the autophagosomal recognition of the inner mitochondrial membrane receptor PHB2. UBQLN2 is required for Parkin-mediated mitophagy and neuronal survival upon mitochondrial damage, and the ALS/FTD pathogenic mutations in UBQLN2 impair mitophagy in primary cultured neurons. Taken together, our findings link dysfunctional mitophagy to UBQLN2-mediated neurodegeneration.
    Keywords:  ALS; Parkin; UBQLN2; mitophagy; ubiquitin
    DOI:  https://doi.org/10.15252/embr.202255859
  5. Biomedicines. 2023 Jul 10. pii: 1952. [Epub ahead of print]11(7):
    The Effects of Serping1 siRNA in α-Synuclein Regulation in MPTP-Induced Parkinson's Disease.
    Min Hyung Seo, Sujung Yeo.
      Our understanding of the gastrointestinal system in the pathophysiology of Parkinson's disease (PD) has grown considerably over the last two decades. Patients with PD experience notable gastrointestinal symptoms, including constipation. In this study, the effects of knocked-down serping1, associated with the contraction and relaxation of smooth muscle and inflammation responses, by applying the serping1 siRNA were investigated in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced PD mice in an α-syn change aspect. In the result, serping1 expression was knocked down by the treatment of serping1 siRNA, and decreased serping1 induced the decrease α-syn in the colon. Furthermore, the changes in α-syn aggregation were also examined in the brain, and alleviated α-syn aggregation was also observed in an serping1 siRNA treatment group. The results indicated that serping1 siRNA could ease synucleinopathy related to the gastrointestinal system in PD. This study also raises the possibility that serping1 siRNA could alleviate α-syn aggregation in striatum and substantia nigra regions of the brain.
    Keywords:  MPTP; Parkinson’s disease; colon; serping1; α-synuclein
    DOI:  https://doi.org/10.3390/biomedicines11071952
  6. Protein Sci. 2023 Jul 29. e4736
    Lipid-induced polymorphic amyloid fibril formation by α-synuclein.
    Bhanu P Singh, Ryan J Morris, Tilo Kunath, Cait E MacPhee, Mathew H Horrocks.
      Many proteins that self-assemble into amyloid and amyloid-like fibres can adopt diverse polymorphic forms. These forms have been observed both in vitro and in vivo and can arise through variations in the steric-zipper interactions between ꞵ-sheets, variations in the arrangements between protofilaments, and differences in the number of protofilaments that make up a given fibre class. Different polymorphs arising from the same precursor molecule not only exhibit different levels of toxicity, but importantly can contribute to different disease conditions. However, the factors which contribute to formation of polymorphic forms of amyloid fibrils are not known. In this work, we show that in the presence of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine, a highly abundant lipid in the plasma membrane of neurons, the aggregation of α-synuclein is markedly accelerated and yields a diversity of polymorphic forms under identical experimental conditions. This morphological diversity includes thin and curly fibrils, helical ribbons, twisted ribbons, nanotubes, and flat sheets. Furthermore, the amyloid fibrils formed incorporate lipids into their structures, which corroborates the previous report of the presence of α-synuclein fibrils with high lipid content in Lewy bodies. Thus, the present study demonstrates that an interface, such as that provided by a lipid membrane, can not only modulate the kinetics of α-synuclein amyloid aggregation but also plays an important role in the formation of morphological variants by incorporating lipid molecules in the process of amyloid fibril formation. This article is protected by copyright. All rights reserved.
    Keywords:  Amyloid polymorphism; Lipid-Protein Interaction; polypeptide self-assembly; protein aggregation; α-synuclein
    DOI:  https://doi.org/10.1002/pro.4736
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:27.