TDP43 and RNA instability in amyotrophic lateral sclerosis

Weskamp, Kaitlin; Barmada, Sami J.

doi:10.1016/j.brainres.2018.01.015

Cited by 45 publications

(45 citation statements)

References 138 publications

(175 reference statements)

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“…TDP-43 binds to Btn1a1 and Xdh mRNA. TDP-43 is a RBP 38 , with the binding motif of the UG-enriched sequence 33,39 regulating RNA in a variety of ways. To decipher the regulatory mechanism of TDP-43 on Btn1a1 and Xdh, we examined whether a UG-or TG-enriched sequences existed in the Btn1a1 and Xdh gene promoter regions, pre-mRNA, and mRNA.…”

Section: Tdp-43 Loss Reduces Btn and Xor Expressionmentioning

confidence: 99%

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Zhao

Hao

et al. 2020

Nat Commun

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Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. However, the underlying molecular mechanism is less clear. Here we report that TDP-43, a RNA-binding protein, underwent positive selection in the mammalian lineage. Furthermore, TDP-43 gene (Tardbp) loss induces accumulation of large lipid droplets and severe lipid secretion deficiency in mammary epithelial cells to outside alveolar lumens, eventually resulting in lactation failure and pup starvation within three weeks postpartum. In human milk samples from lactating women, the expression levels of TDP-43 is positively correlated with higher milk output. Mechanistically, TDP-43 exerts post-transcriptional regulation of Btn1a1 and Xdh mRNA stability, which are required for the secretion of lipid droplets from epithelial cells to the lumen. Taken together, our results highlights the critical role of TDP-43 in milk lipid secretion, providing a potential strategy for the screening and intervention of clinical lactation insufficiency.

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Section: Tdp-43 Loss Reduces Btn and Xor Expressionmentioning

confidence: 99%

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Zhao

Hao

et al. 2020

Nat Commun

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“…Prominent amongst these pathological proteins is TDP-43, which is a highly conserved predominantly nuclear protein with functional roles in RNA metabolism (Ayala et al, 2008; Weskamp and Barmada, 2018). TDP-43 has been reproducibly identified as one of the components of cytosolic protein inclusions, a pathological hallmark in almost all ALS and some FTD cases (known pathologically as frontotemporal lobar degeneration with TDP-43 pathology, FTLD-TDP), irrespective of genetic inheritance or mutation (Neumann et al, 2006, 2007; Wang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD

et al. 2019

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Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing in prevalence but lack targeted therapeutics. Although the pathological mechanisms behind these diseases remain unclear, both ALS and FTD are characterized pathologically by aberrant protein aggregation and inclusion formation within neurons, which correlates with neurodegeneration. Notably, aggregation of several key proteins, including TAR DNA binding protein of 43 kDa (TDP-43), superoxide dismutase 1 (SOD1), and tau, have been implicated in these diseases. Proteomics methods are being increasingly applied to better understand disease-related mechanisms and to identify biomarkers of disease, using model systems as well as human samples. Proteomics-based approaches offer unbiased, high-throughput, and quantitative results with numerous applications for investigating proteins of interest. Here, we review recent advances in the understanding of ALS and FTD pathophysiology obtained using proteomics approaches, and we assess technical and experimental limitations. We compare findings from various mass spectrometry (MS) approaches including quantitative proteomics methods such as stable isotope labeling by amino acids in cell culture (SILAC) and tandem mass tagging (TMT) to approaches such as label-free quantitation (LFQ) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) in studies of ALS and FTD. Similarly, we describe disease-related protein-protein interaction (PPI) studies using approaches including immunoprecipitation mass spectrometry (IP-MS) and proximity-dependent biotin identification (BioID) and discuss future application of new techniques including proximity-dependent ascorbic acid peroxidase labeling (APEX), and biotinylation by antibody recognition (BAR). Furthermore, we explore the use of MS to detect post-translational modifications (PTMs), such as ubiquitination and phosphorylation, of disease-relevant proteins in ALS and FTD. We also discuss upstream technologies that enable enrichment of proteins of interest, highlighting the contributions of new techniques to isolate disease-relevant protein inclusions including flow cytometric analysis of inclusions and trafficking (FloIT). These recently developed approaches, as well as related advances yet to be applied to studies of these neurodegenerative diseases, offer numerous opportunities for discovery of potential therapeutic targets and biomarkers for ALS and FTD.

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“…In 2009, this discovery was followed by the identification of FUS, as another common and abundant RNA‐Binding Protein (RBP) involved in the pathobiology of subsets of familial ALS and sporadic FTLD cases . Since then, the basic properties of both proteins have been under intense study and their potential role in disease has been recently reviewed in many reports .…”

Section: Ftld Molecular Pathologymentioning

confidence: 99%

Review: Molecular pathology of frontotemporal lobar degenerations

Borroni

Alberici

Buratti

2019

Neuropathology Appl Neurobio

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Frontotemporal lobar degeneration (FTLD) is a group of disorders that principally affect the frontal and temporal lobes of the brain. In many parts of the world, FTLD is rapidly becoming a serious health burden on society and, as a result, the molecular mechanisms that underlie its onset and development have been the target of intense research efforts in recent years. Nonetheless, despite crucial pathological and genetic discoveries in this area much is still uncertain about how the many genes associated with this disease cause the observed neurodegeneration. Moreover, it has not been easy to define the molecular mechanisms that account for the clinical and pathological heterogeneity of the various FTLD subtypes, characterized by aggregates of Tau, TAR‐DNA‐Binding Protein‐43 (TDP‐43), and less often Fused in Sarcoma (FUS) protein. In this review, we will examine some of the emerging discoveries in this field: from the recent importance of autoimmunity to the presence of substantial variations in the composition and localization of TDP‐43 and FUS brain aggregates in patients, and how they might affect the course of the disease. All together, these new results demonstrate how the observed clinical heterogeneity underlies considerable complexity at both the molecular and the disease pathway level. A better characterization of all this complexity will be essential for a more accurate stratification of patient cohorts for further studies and, eventually, for trials of therapy.

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TDP43 and RNA instability in amyotrophic lateral sclerosis

Cited by 45 publications

References 138 publications

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD

Review: Molecular pathology of frontotemporal lobar degenerations

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