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  1. Article ; Online: Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.

    Thumbadoo, Kyrah M / Dieriks, Birger V / Murray, Helen C / Swanson, Molly E V / Yoo, Ji Hun / Mehrabi, Nasim F / Turner, Clinton / Dragunow, Michael / Faull, Richard L M / Curtis, Maurice A / Siddique, Teepu / Shaw, Christopher E / Newell, Kathy L / Henden, Lyndal / Williams, Kelly L / Nicholson, Garth A / Scotter, Emma L

    Brain : a journal of neurology

    2024  

    Abstract: Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 ... ...

    Abstract Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases), and p.P497L (three cases)). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates, and p62, in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5), and UBQLN2-linked (n = 8) cases. We differentiate between i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis/and frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.
    Language English
    Publishing date 2024-05-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awae140
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.

    Nementzik, Laura R / Thumbadoo, Kyrah M / Murray, Helen C / Gordon, David / Yang, Shu / Blair, Ian P / Turner, Clinton / Faull, Richard L M / Curtis, Maurice A / McLean, Catriona / Nicholson, Garth A / Swanson, Molly E V / Scotter, Emma L

    Brain pathology (Zurich, Switzerland)

    2023  Volume 34, Issue 3, Page(s) e13230

    Abstract: Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the ...

    Abstract Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and 8 non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates and aggregates containing both proteins in regions of interest to determine how UBQLN2-linked and non-UBQLN2-linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in UBQLN2-linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2-linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in UBQLN2-linked cases maps best to the aggregation of TDP-43.
    MeSH term(s) Humans ; Adaptor Proteins, Signal Transducing/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy-Related Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Mutation ; Transcription Factors/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; DNA-Binding Proteins ; Transcription Factors ; UBQLN2 protein, human ; TARDBP protein, human
    Language English
    Publishing date 2023-12-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1051484-3
    ISSN 1750-3639 ; 1015-6305
    ISSN (online) 1750-3639
    ISSN 1015-6305
    DOI 10.1111/bpa.13230
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3585: 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)

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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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