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  1. Article: Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders.

    De Marchi, Fabiola / Munitic, Ivana / Vidatic, Lea / Papić, Eliša / Rački, Valentino / Nimac, Jerneja / Jurak, Igor / Novotni, Gabriela / Rogelj, Boris / Vuletic, Vladimira / Liscic, Rajka M / Cannon, Jason R / Buratti, Emanuele / Mazzini, Letizia / Hecimovic, Silva

    Biomedicines

    2023  Volume 11, Issue 10

    Abstract: Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in ... ...

    Abstract Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann-Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.
    Language English
    Publishing date 2023-10-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines11102793
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.

    De Marchi, Fabiola / Franjkic, Toni / Schito, Paride / Russo, Tommaso / Nimac, Jerneja / Chami, Anna A / Mele, Angelica / Vidatic, Lea / Kriz, Jasna / Julien, Jean-Pierre / Apic, Gordana / Russell, Robert B / Rogelj, Boris / Cannon, Jason R / Baralle, Marco / Agosta, Federica / Hecimovic, Silva / Mazzini, Letizia / Buratti, Emanuele /
    Munitic, Ivana

    Biomedicines

    2023  Volume 11, Issue 6

    Abstract: Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in ... ...

    Abstract Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.
    Language English
    Publishing date 2023-05-31
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines11061599
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation.

    Dominko, Kristina / Rastija, Ana / Sobocanec, Sandra / Vidatic, Lea / Meglaj, Sarah / Lovincic Babic, Andrea / Hutter-Paier, Birgit / Colombo, Alessio-Vittorio / Lichtenthaler, Stefan F / Tahirovic, Sabina / Hecimovic, Silva

    International journal of molecular sciences

    2021  Volume 22, Issue 24

    Abstract: Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis ... ...

    Abstract Niemann-Pick type C disease (NPC) is a rare inherited neurodegenerative disorder characterized by an accumulation of intracellular cholesterol within late endosomes and lysosomes due to NPC1 or NPC2 dysfunction. In this work, we tested the hypothesis that retromer impairment may be involved in the pathogenesis of NPC and may contribute to increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis observed in NPC disease. Using
    MeSH term(s) Animals ; CHO Cells ; Cells, Cultured ; Cholesterol/metabolism ; Cricetulus ; Disease Models, Animal ; Female ; Humans ; Loss of Function Mutation ; Male ; Membrane Transport Proteins/metabolism ; Mice ; Neurons/cytology ; Neurons/metabolism ; Niemann-Pick C1 Protein/genetics ; Niemann-Pick Disease, Type C/genetics ; Niemann-Pick Disease, Type C/metabolism ; Primary Cell Culture ; Receptors, LDL/metabolism ; Vesicular Transport Proteins/metabolism
    Chemical Substances Membrane Transport Proteins ; Niemann-Pick C1 Protein ; Npc1 protein, mouse ; Receptors, LDL ; Sorl1 protein, mouse ; Vesicular Transport Proteins ; Vps26 protein, mouse ; Vps35 protein, mouse ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2021-12-09
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms222413256
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.

    Colombo, Alessio / Dinkel, Lina / Müller, Stephan A / Sebastian Monasor, Laura / Schifferer, Martina / Cantuti-Castelvetri, Ludovico / König, Jasmin / Vidatic, Lea / Bremova-Ertl, Tatiana / Lieberman, Andrew P / Hecimovic, Silva / Simons, Mikael / Lichtenthaler, Stefan F / Strupp, Michael / Schneider, Susanne A / Tahirovic, Sabina

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1158

    Abstract: Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss ...

    Abstract Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1
    MeSH term(s) Animals ; Blotting, Western ; Cells, Cultured ; Cholesterol/metabolism ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microglia/metabolism ; Myelin Sheath/metabolism ; Niemann-Pick C1 Protein ; Niemann-Pick Disease, Type C/genetics ; Niemann-Pick Disease, Type C/metabolism ; Phagocytosis/genetics ; Phagocytosis/physiology ; Proteomics/methods
    Chemical Substances Intracellular Signaling Peptides and Proteins ; Niemann-Pick C1 Protein ; Npc1 protein, mouse ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2021-02-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; 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/s41467-021-21428-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains.

    Causevic, Mirsada / Dominko, Kristina / Malnar, Martina / Vidatic, Lea / Cermak, Stjepko / Pigoni, Martina / Kuhn, Peer-Hendrik / Colombo, Alessio / Havas, Daniel / Flunkert, Stefanie / McDonald, Jessica / Gunnersen, Jenny M / Hutter-Paier, Birgit / Tahirovic, Sabina / Windisch, Manfred / Krainc, Dimitri / Lichtenthaler, Stefan F / Hecimovic, Silva

    PloS one

    2018  Volume 13, Issue 7, Page(s) e0200344

    Abstract: It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), ...

    Abstract It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4-weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease.
    MeSH term(s) Amyloid Precursor Protein Secretases/metabolism ; Animals ; Aspartic Acid Endopeptidases/metabolism ; Brain/growth & development ; Brain/metabolism ; Brain/pathology ; Disease Models, Animal ; Mice, Inbred BALB C ; Mice, Knockout ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Neurons/pathology ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick Disease, Type C/pathology ; Proteins/genetics ; Proteins/metabolism ; Proteolysis
    Chemical Substances Nerve Tissue Proteins ; Npc1 protein, mouse ; Proteins ; Sez6 protein, mouse ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Bace1 protein, mouse (EC 3.4.23.46)
    Language English
    Publishing date 2018-07-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0200344
    Database MEDical Literature Analysis and Retrieval System OnLINE

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