To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Loganathan, Suvithanandhini; Lehmkuhl, Erik M.; Eck, Randall J.; Zarnescu, Daniela C.

doi:10.3389/fmolb.2019.00154

Cited by 19 publications

(16 citation statements)

References 117 publications

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“…More recently, we demonstrated that other regions, including the RRM motifs, can play an important role in aggregation and pathology (Zacco et al, 2018). This evidence agrees with a role of RNA in the aggregation properties of this protein (Gotor et al, 2020;Loganathan et al, 2020). We also demonstrated that binding to short RNA aptamers can efficiently prevent TDP-43 aggregation (Zacco et al, 2019).…”

Section: Introductionsupporting

confidence: 83%

New lessons on TDP-43 from the killifish N. furzeri

Louka

Bagnoli

Rupert

et al. 2021

Preprint

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Frontotemporal dementia and amyotrophic lateral sclerosis are fatal and incurable neurodegenerative diseases linked to the pathological aggregation of the TDP-43 protein. This is an essential DNA/RNA binding protein involved in transcription regulation, pre-RNA processing and RNA transport. Having suitable animal models to study the mechanisms of TDP-43 aggregation is crucial to develop treatments against disease. We have previously demonstrated that the killifish Nothobranchius furzeri offers the unique advantage as a model system that it is an organism with compressed lifespan and a conserved ageing phenotype that develops within months, making this organism the available shortest-lived vertebrate with a clear ageing phenotype. Here, we show that the two paralogs of TDP-43 from the killifish N. furzeri share high sequence homology with the human protein and recapitulate its cellular and biophysical behaviour. We prove that, during ageing, N. furzeri TDP-43 spontaneously forms insoluble intracellular TDP-43 aggregates that have amyloid characteristics and colocalize with the stress granule core protein G3BP. Our results propose this organism as a valuable model of TDP-43-related pathologies and show that even minute differences between the human and N. furzeri proteins may help to shed new light onto the role of TDP-43 in RNA recognition and granule formation.

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Section: Introductionsupporting

confidence: 83%

New lessons on TDP-43 from the killifish N. furzeri

Louka

Bagnoli

Rupert

et al. 2021

Preprint

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“…PJA1 as demonstrated in the present study might have been the E3 ligase missing in their report. In addition, we observed two types of co-localization of TDP-43 and PJA1 under fluorescence microscopy: perinuclear round fluorescence putatively representing stress granules [34][35][36][37] and cytoplasmic amorphous fluorescence found only in cells infected with PJA1ΔR adenovirus, which were considered to be degraded by WT PJA1. We speculate that PJA1 binds to TDP-43 in stress granules and suppresses the formation of cytoplasmic TDP-43 aggregates, which should be investigated further using stress granule markers to identify co-localization of PJA1 and TDP-43 in these structures.…”

Section: Discussionmentioning

confidence: 89%

“…5D). The former perinuclear fluorescence appeared to localize to stress granules [34][35][36][37] found in cells infected with adenovirus expressing both WT and RING finger domain lacking (ΔR) PJA1, while the latter cytoplasmic aggregates were observed only in cells expressing PJA1ΔR adenovirus, which would be degraded by WT PJA1 (Fig. 5D).…”

Section: Pja1 Binds To Tdp-43 and E2 Ubiquitin Conjugating Enzyme Ube2e3mentioning

confidence: 97%

Praja1 RING‐finger E3 ubiquitin ligase suppresses neuronal cytoplasmic TDP‐43 aggregate formation

et al. 2020

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Transactivation response DNA-binding protein of 43 kDa (TDP-43) is a major constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We have previously shown neuronal cytoplasmic aggregate formation induced by recombinant adenoviruses expressing human wild-type and C-terminal fragment (CTF) TDP-43 under the condition of proteasome inhibition in vitro and in vivo. In the present study, we demonstrated that the formation of the adenoviral TDP-43 aggregates was markedly suppressed in rat neural stem cell-derived neuronal cells by co-infection of an adenovirus expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response. We performed DNA microarray analysis and searched several candidate molecules, located downstream of HSF1, which counteract TDP-43 aggregate formation. Among these, we identified Praja 1 RING-finger E3 ubiquitin ligase (PJA1) as a suppressor of phosphorylation and aggregate formation of TDP-43. Co-immunoprecipitation assay revealed that PJA1 binds to CTF TDP-43 and the E2-conjugating enzyme UBE2E3. PJA1 also suppressed formation of cytoplasmic phosphorylated TDP-43 aggregates in mouse facial motor neurons in vivo. Furthermore, phosphorylated TDP-43 aggregates were detected in PJA1immunoreactive human ALS motor neurons. These results indicate that PJA1 is one of the principal E3 ubiquitin ligases for TDP-43 to counteract its aggregation propensity and could be a potential therapeutic target for ALS and FTLD.

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“…It binds and regulates UG-rich RNAs and TG-rich single stranded DNA, impacting on functions such as splicing, transportation and degradation [8][9][10], and thereby plays a key role in local protein translation in neuronal axons and neurites [11,12]. Like many RBPs, TDP-43 can also form cytoplasmic stress granules (SGs) in response to cellular stress, which safeguards the essential mRNA from degradation and promotes rapid recovery when the stress is removed [13]. Crucially, homozygous TDP-43 knockout mice are not viable indicating it is an essential protein for development and survival [14].…”

Section: Tdp-43 In Healthmentioning

confidence: 99%

Mechanisms of TDP-43 Proteinopathy Onset and Propagation

Chen

Mitchell

2021

IJMS

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TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease.

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To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Cited by 19 publications

References 117 publications

New lessons on TDP-43 from the killifish N. furzeri

New lessons on TDP-43 from the killifish N. furzeri

Praja1 RING‐finger E3 ubiquitin ligase suppresses neuronal cytoplasmic TDP‐43 aggregate formation

Mechanisms of TDP-43 Proteinopathy Onset and Propagation

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