Publisher Correction: TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

White, Matthew A.; Kim, Eosu; Duffy, Amanda; Adalbert, Róbert; Phillips, Benjamin U.; Peters, Owen M.; Stephenson, Jodie; Yang, Sujeong; Massenzio, Francesca; Lin, Ziqiang; Andrews, Simon; Segonds‐Pichon, Anne; Metterville, Jake; Saksida, Lisa M.; Mead, Richard; Ribchester, Richard R.; Barhomi, Youssef; Serre, T.; Coleman, Michael P.; Fallon, Justin R.; Bussey, Timothy J.; Brown, Robert H.; Sreedharan, Jemeen

doi:10.1038/s41593-018-0160-y

Cited by 9 publications

(3 citation statements)

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“…Several knock-in mouse models expressing mutant TDP-43 display a range of phenotypes depending on the mutation, but most behavioural phenotypes are quite subtle and occur at a very-late stage [ 254 , 257 , 261 , 262 ]. For example, the TDP-43 Q331K knock-in mouse model does not display significant motor phenotype whereas the TDP-43 Q331K transgenic mouse display some, but not robust, motor deficits [ 31 , 263 ]. This difference may be due to synergistic effects of the TDP-43 mutation and overexpression in the transgenic model.…”

Section: Main Textmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

208

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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Section: Main Textmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

208

170

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“…Manual NMJ assessment is performed differently between laboratories, impacting cross-comparison studies on neuromuscular innervation 7 , 28 , 30 , 32 , 34 , 35 , 37 , 59 – 61 . Manual assessment had limitations when for NMJ metanalysis.…”

Section: Resultsmentioning

confidence: 99%

“…This apparent discrepancy with our results may be explained, in part, by the sex of mice used, muscle fibretype composition, muscle studied and cut-off parameters used for full, partial and denervation NMJ status 6 , 61 . Moreover, the methodology of manual NMJ analysis in mouse models varies across laboratories, and different cut-off parameters for NMJ innervation status limit cross-comparison studies 6 , 7 , 10 , 25 , 26 , 30 , 32 – 33 , 59 , 60 .…”

Section: Discussionmentioning

confidence: 99%

NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease

Maza

Jarvis

Lee

et al. 2021

Sci Rep

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The neuromuscular junction (NMJ) is the peripheral synapse formed between a motor neuron axon terminal and a muscle fibre. NMJs are thought to be the primary site of peripheral pathology in many neuromuscular diseases, but innervation/denervation status is often assessed qualitatively with poor systematic criteria across studies, and separately from 3D morphological structure. Here, we describe the development of ‘NMJ-Analyser’, to comprehensively screen the morphology of NMJs and their corresponding innervation status automatically. NMJ-Analyser generates 29 biologically relevant features to quantitatively define healthy and aberrant neuromuscular synapses and applies machine learning to diagnose NMJ degeneration. We validated this framework in longitudinal analyses of wildtype mice, as well as in four different neuromuscular disease models: three for amyotrophic lateral sclerosis (ALS) and one for peripheral neuropathy. We showed that structural changes at the NMJ initially occur in the nerve terminal of mutant TDP43 and FUS ALS models. Using a machine learning algorithm, healthy and aberrant neuromuscular synapses are identified with 95% accuracy, with 88% sensitivity and 97% specificity. Our results validate NMJ-Analyser as a robust platform for systematic and structural screening of NMJs, and pave the way for transferrable, and cross-comparison and high-throughput studies in neuromuscular diseases.

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Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex

Koike

Sugai

Hara

et al. 2021

Preprint

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In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43) forms aggregates in the motor cortex of the aging brain. This aggregate formation may be triggered by the increase in TDP-43 levels with aging. However, the amount of TDP-43 is autoregulated by the alternative splicing of the TARDBP 3’UTR, and its relationship with aging remains unresolved. Since DNA methylation is altered during aging, we hypothesized that 3’UTR methylation is also altered in the aging motor cortex, disrupting this autoregulatory system and increasing TDP-43 levels. We found that DNA demethylation in the autoregulatory region of TDP-43 reduced alternative splicing and increased TDP-43 expression. Furthermore, in the human motor cortex, we found that this region was demethylated with age and that the expression of TDP-43 increased. The dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and system selectivity in ALS.

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Publisher Correction: TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

Cited by 9 publications

References 0 publications

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease

Age-related demethylation of the TDP-43 autoregulatory region in the human motor cortex

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