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; Aalderink, Miranda; Siemens, Andrew; Fan, Vicky; Wu, Jane Y.; Mee, Edward; Faull, Richard L.M.; Dragunow, Mike

doi:10.1016/j.mcn.2022.103768

Cited by 7 publications

(8 citation statements)

References 99 publications

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“…RNA samples were extracted from paired samples (scr and siTDP) from 12 donor cell lines ( Table S1 ). Of these RNA samples, 9 pairs were sent for RNA-sequencing as reported previously (47) and 3 pairs (extracted from cell lines from different donors from those sent for sequencing) were used as a ‘replication cohort’ to validate RNA-sequencing results by qPCR. Successful TDP-43 depletion from the RNA-sequencing cohort was demonstrated by differential gene expression analysis using the DESeq2 package in R software ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Tissue from the middle temporal gyrus (MTG) and motor cortex (MC) was processed for the isolation of mixed glial cultures, with early passages (up to passage 5) containing a mixture of pericytes, astrocytes and microglia, as previously described (91). Cells were maintained as described previously (46, 47). Due to the proliferation of pericytes, which overgrow the non-proliferative glial cells, later passage cultures contain almost exclusively pericytes (43–45).…”

Section: Methodsmentioning

confidence: 99%

“…Due to the proliferation of pericytes, which overgrow the non-proliferative glial cells, later passage cultures contain almost exclusively pericytes (43)(44)(45). To examine TDP-43 loss of function (LOF) in pericytes, cells were transfected with scrambled (scr) small interfering RNA (siRNA) or siRNA against TARDBP (siTDP) as described previously (47).…”

Section: Donor Pericyte Line Isolation Culture and Transfectionmentioning

confidence: 99%

“…Pericytes are critical to BBB integrity by stabilizing endothelial tight junctions and suppressing transcytosis across endothelia (37)(38)(39)(40). In addition to being a critical contributor to BBB structural integrity, pericytes also have the ability to release cytokines that mediate leukocyte extravasation and propagate neuroinflammation (41)(42)(43)(44)(45)(46), and the production of the cytokine IL-6 by pericytes is suppressed with TDP-43 knockdown (47). Loss of pericytes and breakdown of the BBB has been demonstrated in ALS patients and ALS animal models (40,(48)(49)(50)(51)(52).…”

Section: Introductionmentioning

confidence: 99%

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A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cao

Ryan

et al. 2023

Preprint

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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 exon changes are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. Here, we investigated TDP-43 loss of function by depleting TARDBP from human post-mortem brain pericytes and identifying differential exon usage events with RNA-sequencing analysis. Differential exon usage events validated by qPCR were compiled into a panel with other well-established TDP-43 loss-of-function exon markers and then tested in ALS and control motor cortex tissue. We find that profiles of TDP-43-related cryptic exons and changed exon usage discriminate ALS brain tissue from controls, and propose that splicing panels may have predictive value for therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Donor Pericyte Line Isolation Culture and Transfectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cao

Ryan

et al. 2023

Preprint

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“…Notably, downregulation of TDP-43 was also associated with strongly suppression of IL-6 production after IL-1β and TGF-β1 stimulation in cultured primary human brain pericytes. Scotter and collaborators have hypothesized that this could be due to the TDP-43 dependent splicing regulation of hnRNP D [ 107 ]. These results have been supported by two recent publications regarding the role of Protein tyrosine phosphatase 1B (PTP1B) inhibition in attenuating astrocytes cell death as a consequence of TDP-43 mediated suppression of IL-6 [ 108 ], as well as the role of TDP-43 as a scaffold protein of the interleukin-6 and -10 splicing activating compartment (InSAC) [ 109 ].…”

Section: The Role Of Neuroinflammation In Viral Infection and Neurode...mentioning

confidence: 99%

Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies

Rahic

Buratti

Cappelli

2023

IJMS

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Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler’s murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions.

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A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cao

Ryan

et al. 2023

Neurobiology of Disease

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The amyotrophic lateral sclerosis-linked protein TDP-43 regulates interleukin-6 cytokine production by human brain pericytes

Cited by 7 publications

References 99 publications

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Reviewing the Potential Links between Viral Infections and TDP-43 Proteinopathies

A panel of TDP-43-regulated splicing events verifies loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

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