Cryptic exon splicing function of TARDBP interacts with autophagy in nervous tissue

Torres, Pascual; Ramírez‐Núñez, Omar; Romero-Guevara, Ricardo; Barés, Gisel; Granado-Serrano, Ana Belén; Ayala, Victòria; Boada, Jordi; Fontdevila, Laia; Povedano, Mònica; Sanchı́s, Daniel; Pamplona, Reinald; Ferrer, Isidro; Portero‐Otín, Manuel

doi:10.1080/15548627.2018.1474311

Cited by 50 publications

(45 citation statements)

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“…TARDBP knockout mice show embryonic lethality [68, 130] and partial knockdown of TDP-43 results in motor deficits [68, 165] and motor neuron loss in mice [165]. Several recent cell-based studies have reported that TDP-43 knockdown leads to incorporation of cryptic exons [58, 76, 140, 142], also detected in FTD/ALS patient cerebral cortical areas with substantial TDP-43 aggregation [76], in AD with TDP-43 proteinopathy [140], and in motor cortex, spinal cord, brainstem and occipital cortex from patients with ALS [146]. Incorporation of cryptic exons in neurons lacking nuclear TDP-43 may, in turn, reduce expression of essential proteins via nonsense-mediated decay of aberrant transcripts; this process is likely involved in both sporadic and C9orf72 -FTD/ALS.…”

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

“…Incorporation of cryptic exons in neurons lacking nuclear TDP-43 may, in turn, reduce expression of essential proteins via nonsense-mediated decay of aberrant transcripts; this process is likely involved in both sporadic and C9orf72 -FTD/ALS. Indeed, a recent cell-based study found expression of cryptic exon-containing ATG4B mRNA, accompanied by reduced ATG4B protein, in the context of TARDBP knockdown [146]. “TDP-43 depletion,” the loss of TDP-43 from neuronal nuclei in the absence of a visible, well-developed cytoplasmic inclusion, is a recently described feature of C9orf72 -bvFTD [155] and sporadic ALS [10, 11], and may occur early in the disease process.…”

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

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C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

et al. 2018

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What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

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Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

et al. 2018

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“…The involvement of TDP-43 was first reported in nuclear RNA transcription, mRNA stability regulation and modulation of mRNA splicing [9, 10, 12]. In addition, TDP-43’s role in a wide variety of cellular events, such as nucleocytoplasmic transport [51], mitochondrial stability [31], and autophagy pathways [6, 67], are beginning to emerge.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.

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“…Up to date, no previous evidence of its involvement in this disease were known, except with the fact that PKC levels were increased in ALS patients [29]. The involvement of the potential loss of PKCßII in ALS pathogenesis can be diverse, as this protein interacts with mitochondria [30], and with autophagic function [31], to name a few, and both elements are involved in ALS [32,33] Other changes in lipid components of nuclei include plasmalogens. These membrane glycerophospholipids contain a fatty alcohol with a vinyl-ether bond at the sn-1 position, and they are enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone.…”

Section: Discussionmentioning

confidence: 99%

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

Ramírez‐Núñez¹,

Jové²,

Torres³

et al. 2019

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In this pilot study, we show that nuclei in spinal cord from ALS patients exhibit a differential lipidomic signature. Among the differential lipid species we could annotate 41 potential identities. These comprise membrane-bound lipids such as phosphatidylethanolamines -including plasmalogens-and phosphatidylcholines but also other lipid classes such as glycosphingolipids, diacylglycerols, and triacylglycerides (potentially present as nuclear lipid droplets). These results were orthogonally validated by showing loss of alkyldihydroxyacetonephosphate synthase (AGPS), a key peroxisomal enzyme in plasmalogen synthesis, both in ALS necropsy samples, in human motor neurons derived from iPSC from ALS patients and in hSOD-G93A transgenic mice. Further, diacylglycerol content changes were associated to ALS-linked variations in relatedenzymes, such as phospholipase C ßI (PLCßI), the source of nuclear diacylglycerol, and protein kinase CßII (PKCßII), whose function partially depends on nuclei concentration of diacylglycerol. These results point out for not only a role of nuclear membrane lipids but also to lipids present in the nucleoplasm, suggesting an undisclosed role for this part of the subcellular lipidome in ALS pathophysiology.

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Cryptic exon splicing function of TARDBP interacts with autophagy in nervous tissue

Cited by 50 publications

References 15 publications

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

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