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  1. Article ; Online: Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration.

    Festa, Beatrice Paola / Siddiqi, Farah H / Jimenez-Sanchez, Maria / Won, Hyeran / Rob, Matea / Djajadikerta, Alvin / Stamatakou, Eleanna / Rubinsztein, David C

    Neuron

    2023  Volume 111, Issue 13, Page(s) 2021–2037.e12

    Abstract: In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated ... ...

    Abstract In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington's disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models.
    MeSH term(s) Mice ; Animals ; Microglia/metabolism ; Signal Transduction ; Autophagy ; Neurodegenerative Diseases/metabolism ; Proteins/metabolism ; Huntington Disease/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism
    Chemical Substances Proteins ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
    Language English
    Publishing date 2023-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2023.04.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2496: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 92: Show issues

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  2. Article ; Online: Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases.

    Djajadikerta, Alvin / Keshri, Swati / Pavel, Mariana / Prestil, Ryan / Ryan, Laura / Rubinsztein, David C

    Journal of molecular biology

    2019  Volume 432, Issue 8, Page(s) 2799–2821

    Abstract: Autophagy is a major, conserved cellular pathway by which cells deliver cytoplasmic contents to lysosomes for degradation. Genetic studies have revealed extensive links between autophagy and neurodegenerative disease, and disruptions to autophagy may ... ...

    Abstract Autophagy is a major, conserved cellular pathway by which cells deliver cytoplasmic contents to lysosomes for degradation. Genetic studies have revealed extensive links between autophagy and neurodegenerative disease, and disruptions to autophagy may contribute to pathology in some cases. Autophagy degrades many of the toxic, aggregate-prone proteins responsible for such diseases, including mutant huntingtin (mHTT), alpha-synuclein (α-syn), tau, and others, raising the possibility that autophagy upregulation may help to reduce levels of toxic protein species, and thereby alleviate disease. This review examines autophagy induction as a potential therapy in several neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, polyglutamine diseases, and amyotrophic lateral sclerosis (ALS). Evidence in cells and in vivo demonstrates promising results in many disease models, in which autophagy upregulation is able to reduce the levels of toxic proteins, ameliorate signs of disease, and delay disease progression. However, the effective therapeutic use of autophagy induction requires detailed knowledge of how the disease affects the autophagy-lysosome pathway, as activating autophagy when the pathway cannot go to completion (e.g., when lysosomal degradation is impaired) may instead exacerbate disease in some cases. Investigating the interactions between autophagy and disease pathogenesis is thus a critical area for further research.
    MeSH term(s) Animals ; Autophagy ; Autophagy-Related Proteins/metabolism ; Humans ; Molecular Targeted Therapy ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurodegenerative Diseases/therapy ; Signal Transduction
    Chemical Substances Autophagy-Related Proteins
    Language English
    Publishing date 2019-12-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2019.12.035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance.

    Wrobel, Lidia / Hill, Sandra M / Djajadikerta, Alvin / Fernandez-Estevez, Marian / Karabiyik, Cansu / Ashkenazi, Avraham / Barratt, Victoria J / Stamatakou, Eleanna / Gunnarsson, Anders / Rasmusson, Timothy / Miele, Eric W / Beaton, Nigel / Bruderer, Roland / Feng, Yuehan / Reiter, Lukas / Castaldi, M Paola / Jarvis, Rebecca / Tan, Keith / Bürli, Roland W /
    Rubinsztein, David C

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 4146

    Abstract: Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington's disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially ... ...

    Abstract Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington's disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases.
    MeSH term(s) Adenosine Triphosphatases/metabolism ; Autophagy ; Cell Cycle Proteins/metabolism ; Humans ; Neurodegenerative Diseases/genetics ; Phosphatidylinositol Phosphates ; Proteasome Endopeptidase Complex/metabolism ; Valosin Containing Protein/genetics ; Valosin Containing Protein/metabolism
    Chemical Substances Cell Cycle Proteins ; Phosphatidylinositol Phosphates ; phosphatidylinositol 3-phosphate ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Adenosine Triphosphatases (EC 3.6.1.-) ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6)
    Language English
    Publishing date 2022-07-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-31905-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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