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  1. Article ; Online: Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 - meta-analysis and interactive graphical database.

    Cao, Maize C / Scotter, Emma L

    Disease models & mechanisms

    2022  Volume 15, Issue 9

    Abstract: TDP-43 proteinopathy is the major pathology in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal dementia (FTD). Mounting evidence implicates loss of normal TDP-43 RNA-processing function as a key pathomechanism. However, the RNA ... ...

    Abstract TDP-43 proteinopathy is the major pathology in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal dementia (FTD). Mounting evidence implicates loss of normal TDP-43 RNA-processing function as a key pathomechanism. However, the RNA targets of TDP-43 differ by report, and have never been formally collated or compared between models and disease, hampering understanding of TDP-43 function. Here, we conducted re-analysis and meta-analysis of publicly available RNA-sequencing datasets from six TDP-43-knockdown models, and TDP-43-immunonegative neuronal nuclei from ALS/FTD brain, to identify differentially expressed genes (DEGs) and differential exon usage (DEU) events. There was little overlap in DEGs between knockdown models, but PFKP, STMN2, CFP, KIAA1324 and TRHDE were common targets and were also differentially expressed in TDP-43-immunonegative neurons. DEG enrichment analysis revealed diverse biological pathways including immune and synaptic functions. Common DEU events in human datasets included well-known targets POLDIP3 and STMN2, and novel targets EXD3, MMAB, DLG5 and GOSR2. Our interactive database (https://www.scotterlab.auckland.ac.nz/research-themes/tdp43-lof-db/) allows further exploration of TDP-43 DEG and DEU targets. Together, these data identify TDP-43 targets that can be exploited therapeutically or used to validate loss-of-function processes. This article has an associated First Person interview with the first author of the paper.
    MeSH term(s) Amyotrophic Lateral Sclerosis/pathology ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/pathology ; Humans ; RNA
    Chemical Substances DNA-Binding Proteins ; TARDBP protein, human ; RNA (63231-63-0)
    Language English
    Publishing date 2022-09-13
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.049418
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue.

    Cao, Maize C / Ryan, Brigid / Wu, Jane / Curtis, Maurice A / Faull, Richard L M / Dragunow, Mike / Scotter, Emma L

    Neurobiology of disease

    2023  Volume 185, Page(s) 106245

    Abstract: TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the ... ...

    Abstract TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and differential exon usage are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. In this brief report, we identified markers of TDP-43 loss of function by depleting TARDBP from post-mortem human brain pericytes, a manipulable in vitro primary human brain cell model, and identifying differential exon usage events with bulk RNA-sequencing analysis. We present these data in an interactive database (https://www.scotterlab.auckland.ac.nz/research-themes/tdp43-lof-db-v2/) together with seven other TDP-43-depletion datasets we meta-analysed previously, for user analysis of differential expression and splicing signatures. Differential exon usage events that were validated by qPCR were then compiled into a 'differential exon usage panel' with other well-established TDP-43 loss-of-function exon markers. This differential exon usage panel was investigated in ALS and control motor cortex tissue to verify whether, and to what extent, TDP-43 loss of function occurs in ALS. We find that profiles of TDP-43-regulated cryptic exons, changed exon usage and changed 3' UTR usage discriminate ALS brain tissue from controls, verifying that TDP-43 loss of function occurs in ALS. We propose that TDP-43-regulated splicing events that occur in brain tissue will have promise as predictors of disease.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; RNA ; RNA Splicing
    Chemical Substances DNA-Binding Proteins ; RNA (63231-63-0) ; TARDBP protein, human
    Language English
    Publishing date 2023-07-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1211786-9
    ISSN 1095-953X ; 0969-9961
    ISSN (online) 1095-953X
    ISSN 0969-9961
    DOI 10.1016/j.nbd.2023.106245
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4444: 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)
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  3. Article ; Online: Microglial CD68 and L-ferritin upregulation in response to phosphorylated-TDP-43 pathology in the amyotrophic lateral sclerosis brain.

    Swanson, Molly E V / Mrkela, Miran / Murray, Helen C / Cao, Maize C / Turner, Clinton / Curtis, Maurice A / Faull, Richard L M / Walker, Adam K / Scotter, Emma L

    Acta neuropathologica communications

    2023  Volume 11, Issue 1, Page(s) 69

    Abstract: Microglia, the innate immune cells of the brain, are activated by damage or disease. In mouse models of amyotrophic lateral sclerosis (ALS), microglia shift from neurotrophic to neurotoxic states with disease progression. It remains unclear how human ... ...

    Abstract Microglia, the innate immune cells of the brain, are activated by damage or disease. In mouse models of amyotrophic lateral sclerosis (ALS), microglia shift from neurotrophic to neurotoxic states with disease progression. It remains unclear how human microglia change relative to the TAR DNA-binding protein 43 (TDP-43) aggregation that occurs in 97% of ALS cases. Here we examine spatial relationships between microglial activation and TDP-43 pathology in brain tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from the Neurological Foundation Human Brain Bank was obtained from 10 control and 10 ALS cases in parallel with brain tissue from a bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at disease onset, early disease, and late disease stages. The spatiotemporal relationship between microglial activation and ALS pathology was determined by investigating microglial functional marker expression in brain regions with low and high TDP-43 burden at end-stage human disease: hippocampus and motor cortex, respectively. Sections were immunohistochemically labelled with a two-round multiplexed antibody panel against; microglial functional markers (L-ferritin, HLA-DR, CD74, CD68, and Iba1), a neuronal marker, an astrocyte marker, and pathological phosphorylated TDP-43 (pTDP-43). Single-cell levels of microglial functional markers were quantified using custom analysis pipelines and mapped to anatomical regions and ALS pathology. We identified a significant increase in microglial Iba1 and CD68 expression in the human ALS motor cortex, with microglial CD68 being significantly correlated with pTDP-43 pathology load. We also identified two subpopulations of microglia enriched in the ALS motor cortex that were defined by high L-ferritin expression. A similar pattern of microglial changes was observed in the rNLS mouse, with an increase first in CD68 and then in L-ferritin expression, with both occurring only after pTDP-43 inclusions were detectable. Our data strongly suggest that microglia are phagocytic at early-stage ALS but transition to a dysfunctional state at end-stage disease, and that these functional states are driven by pTDP-43 aggregation. Overall, these findings enhance our understanding of microglial phenotypes and function in ALS.
    MeSH term(s) Humans ; Mice ; Animals ; Amyotrophic Lateral Sclerosis/pathology ; Microglia/metabolism ; Apoferritins/metabolism ; Up-Regulation ; Brain/pathology ; DNA-Binding Proteins/metabolism
    Chemical Substances Apoferritins (9013-31-4) ; DNA-Binding Proteins ; TDP-43 protein, mouse
    Language English
    Publishing date 2023-04-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-023-01561-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The amyotrophic lateral sclerosis-linked protein TDP-43 regulates interleukin-6 cytokine production by human brain pericytes.

    Scotter, Emma L / Cao, Maize C / Jansson, Deidre / Rustenhoven, Justin / Smyth, Leon C D / Aalderink, Miranda C / Siemens, Andrew / Fan, Vicky / Wu, Jane / Mee, Edward W / Faull, Richard L M / Dragunow, Mike

    Molecular and cellular neurosciences

    2022  Volume 123, Page(s) 103768

    Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal movement disorder involving degeneration of motor neurons through dysfunction of the RNA-binding protein TDP-43. Pericytes, the perivascular cells of the blood-brain, blood-spinal cord, and blood-CSF ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal movement disorder involving degeneration of motor neurons through dysfunction of the RNA-binding protein TDP-43. Pericytes, the perivascular cells of the blood-brain, blood-spinal cord, and blood-CSF barriers also degenerate in ALS. Indeed, pericytes are among the earliest cell types to show gene expression changes in pre-symptomatic animal models of ALS. This suggests that pericyte degeneration precedes neurodegeneration and may involve pericyte cell-autonomous TDP-43 dysfunction. Here we determined the effect of TDP-43 dysfunction in human brain pericytes on interleukin 6 (IL-6), a critical secreted inflammatory mediator reported to be regulated by TDP 43. Primary human brain pericytes were cultured from biopsy tissue from epilepsy surgeries and TDP-43 was silenced using siRNA. TDP-43 silencing of pericytes stimulated with pro-inflammatory cytokines, interleukin-1β or tumour necrosis factor alpha, robustly suppressed the induction of IL-6 transcript and protein. IL-6 regulation by TDP-43 did not involve the assembly of TDP-43 nuclear splicing bodies, and did not occur via altered splicing of IL6. Instead, transcriptome-wide analysis by RNA-Sequencing identified a poison exon in the IL6 destabilising factor HNRNPD (AUF1) as a splicing target of TDP-43. Our data support a model whereby TDP-43 silencing favours destabilisation of IL6 mRNA, via enhanced AU-rich element-mediated decay by HNRNP/AUF1. This suggests that cell-autonomous deficits in TDP-43 function in human brain pericytes would suppress their production of IL-6. Given the importance of the blood-brain and blood-spinal cord barriers in maintaining motor neuron health, TDP-43 in human brain pericytes may represent a cellular target for ALS therapeutics.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/metabolism ; Brain/metabolism ; Cytokines/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression ; Interleukin-6/metabolism ; Pericytes/metabolism ; Pericytes/pathology ; Spinal Cord/metabolism
    Chemical Substances Cytokines ; DNA-Binding Proteins ; Interleukin-6 ; TARDBP protein, human
    Language English
    Publishing date 2022-08-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1046640-x
    ISSN 1095-9327 ; 1044-7431
    ISSN (online) 1095-9327
    ISSN 1044-7431
    DOI 10.1016/j.mcn.2022.103768
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3035: 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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  5. Article ; Online: Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis.

    Cao, Maize C / Cawston, Erin E / Chen, Grace / Brooks, Collin / Douwes, Jeroen / McLean, Dave / Graham, E Scott / Dragunow, Mike / Scotter, Emma L

    BMC neurology

    2022  Volume 22, Issue 1, Page(s) 216

    Abstract: Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive neurological disorder. Biomarkers are critical to understanding disease causation, monitoring disease progression and assessing the efficacy of treatments. However, robust ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive neurological disorder. Biomarkers are critical to understanding disease causation, monitoring disease progression and assessing the efficacy of treatments. However, robust peripheral biomarkers are yet to be identified. Neuroinflammation and breakdown of the blood-brain barrier (BBB) are common to familial and sporadic ALS and may produce a unique biomarker signature in peripheral blood. Using cytometric bead array (n = 15 participants per group (ALS or control)) and proteome profiling (n = 6 participants per group (ALS or control)), we assessed a total of 106 serum cytokines, growth factors, and BBB breakdown markers in the serum of control and ALS participants. Further, primary human brain pericytes, which maintain the BBB, were used as a biosensor of inflammation following pre-treatment with ALS serum. Principal components analysis of all proteome profile data showed no clustering of control or ALS sera, and no individual serum proteins met the threshold for statistical difference between ALS and controls (adjusted P values). However, the 20 most changed proteins between control and ALS sera showed a medium effect size (Cohen's d = 0.67) and cluster analysis of their levels together identified three sample subsets; control-only, mixed control-ALS, and ALS-only. These 20 proteins were predominantly pro-angiogenic and growth factors, including fractalkine, BDNF, EGF, PDGF, Dkk-1, MIF and angiopoietin-2. S100β, a protein highly concentrated in glial cells and therefore a marker of BBB leakage when found in blood, was unchanged in ALS serum, suggesting that serum protein profiles were reflective of peripheral rather than CNS biofluids. Finally, primary human brain pericytes remained proliferative and their secretome was unchanged by chronic exposure to ALS serum. Our exploratory study suggests that individual serum cytokine levels may not be robust biomarkers in small studies of ALS, but that larger studies using multiplexed analysis of pro-angiogenic and growth factors may identify a peripheral signature of ALS pathogenesis.
    MeSH term(s) Amyotrophic Lateral Sclerosis/pathology ; Biomarkers ; Blood-Brain Barrier/metabolism ; Cytokines ; Humans ; Intercellular Signaling Peptides and Proteins ; Neuroinflammatory Diseases ; Proteome/metabolism
    Chemical Substances Biomarkers ; Cytokines ; Intercellular Signaling Peptides and Proteins ; Proteome
    Language English
    Publishing date 2022-06-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041347-6
    ISSN 1471-2377 ; 1471-2377
    ISSN (online) 1471-2377
    ISSN 1471-2377
    DOI 10.1186/s12883-022-02730-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Motor neuron disease mortality rates in New Zealand 1992-2013.

    Cao, Maize C / Chancellor, Andrew / Charleston, Alison / Dragunow, Mike / Scotter, Emma L

    Amyotrophic lateral sclerosis & frontotemporal degeneration

    2018  Volume 19, Issue 3-4, Page(s) 285–293

    Abstract: Background: We determined the mortality rates of motor neuron disease (MND) in New Zealand over 22 years from 1992 to 2013. Previous studies have found an unusually high and/or increasing incidence of MND in certain regions of New Zealand; however, no ... ...

    Abstract Background: We determined the mortality rates of motor neuron disease (MND) in New Zealand over 22 years from 1992 to 2013. Previous studies have found an unusually high and/or increasing incidence of MND in certain regions of New Zealand; however, no studies have examined MND rates nationwide to corroborate this.
    Methods: Death certificate data coded G12.2 by International Classification of Diseases (ICD)-10 coding, or 335.2 by ICD-9 coding were obtained. These codes specify amyotrophic lateral sclerosis, progressive bulbar palsy, or other motor neuron diseases as the underlying cause of death. Mortality rates for MND deaths in New Zealand were age-standardized to the European Standard Population and compared with rates from international studies that also examined death certificate data and were age-standardized to the same standard population.
    Results and conclusion: The age-standardized mortality from MND in New Zealand was 2.3 per 100,000 per year from 1992-2007 and 2.8 per 100,000 per year from 2008-2013. These rates were 3.3 and 4.0 per 100,000 per year, respectively, for the population 20 years and older. The increase in rate between these two time periods was likely due to changes in MND death coding from 2008. Contrary to a previous regional study of MND incidence, nationwide mortality rates did not increase steadily over this time period once aging was accounted for. However, New Zealand MND mortality rate was higher than comparable studies we examined internationally (mean 1.67 per 100,000 per year), suggesting that further analysis of MND burden in New Zealand is warranted.
    MeSH term(s) Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Death Certificates ; Female ; Humans ; International Classification of Diseases ; Longitudinal Studies ; Male ; Meta-Analysis as Topic ; Middle Aged ; Motor Neuron Disease/epidemiology ; Motor Neuron Disease/mortality ; New Zealand/epidemiology ; Retrospective Studies ; Sex Factors
    Language English
    Publishing date 2018-01-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2705049-X
    ISSN 2167-9223 ; 2167-8421
    ISSN (online) 2167-9223
    ISSN 2167-8421
    DOI 10.1080/21678421.2018.1432660
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5874: 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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