TDP-43 regulates transcription at protein-coding genes and Alu retrotransposons

Morera, Andrés A.; Ahmed, Nasiha; Schwartz, Jacob C.

doi:10.1016/j.bbagrm.2019.194434

Cited by 23 publications

(27 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, in one of the latest studies, data were obtained regarding the inhibitory effect of TDP-43 on L1 activity and its absence was found to increase the level of L1 retrotranspositions by chromatin decompactivation [412]. Despite this, other studies obtained different results, showing that TDP-43 regulates the transcription of many genes and retrotransposons of Alu elements, and does not affect the activity of L1 elements [413,414]. In addition, an increase in HERV-K retroviral repeats was noted, while no changes in L1 activity were detected in lateral amyotrophic sclerosis [415,416].…”

Section: Factors Affecting Changes In L1 Regulation In Neuropsychiatric Diseasesmentioning

confidence: 99%

Factors Regulating the Activity of LINE1 Retrotransposons

Protasova

Andreeva

Rogaev

2021

Genes

View full text Add to dashboard Cite

LINE-1 (L1) is a class of autonomous mobile genetic elements that form somatic mosaicisms in various tissues of the organism. The activity of L1 retrotransposons is strictly controlled by many factors in somatic and germ cells at all stages of ontogenesis. Alteration of L1 activity was noted in a number of diseases: in neuropsychiatric and autoimmune diseases, as well as in various forms of cancer. Altered activity of L1 retrotransposons for some pathologies is associated with epigenetic changes and defects in the genes involved in their repression. This review discusses the molecular genetic mechanisms of the retrotransposition and regulation of the activity of L1 elements. The contribution of various factors controlling the expression and distribution of L1 elements in the genome occurs at all stages of the retrotransposition. The regulation of L1 elements at the transcriptional, post-transcriptional and integration into the genome stages is described in detail. Finally, this review also focuses on the evolutionary aspects of L1 accumulation and their interplay with the host regulation system.

show abstract

Section: Factors Affecting Changes In L1 Regulation In Neuropsychiatric Diseasesmentioning

confidence: 99%

Factors Regulating the Activity of LINE1 Retrotransposons

Protasova

Andreeva

Rogaev

2021

Genes

View full text Add to dashboard Cite

show abstract

“…In the cytoplasm, TDP-43 regulates stress granule dynamics [ 21 , 25 , 46 , 72 ] as well as axonal and dendritic mRNA localization and translation [ 1 , 12 , 15 ]. In disease, TDP-43 is depleted from the nucleus, causing splicing defects, derepression of cryptic exons [ 57 ] and increased retrotransposon expression [ 49 , 61 , 75 , 103 ]. TDP-43 has been shown to induce toxicity through both nuclear loss-of-function and cytoplasmic gain-of-function mechanisms [ 93 , 110 , 113 ].…”

Section: Introductionmentioning

confidence: 99%

TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Lehmkuhl

Loganathan

Alsop

et al. 2021

acta neuropathol commun

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.

show abstract

“…Biomolecular condensates containing protein, RNA, and other nucleic acids [ 1 ] are formed by LLPS under changing endogenous or exogenous conditions, including stress responses [ 3 ] and signal transduction [ 4 , 5 ], as well as genome expression, organization and repair [ 6 ]. In eukaryotes, gene transcription is executed by transcription factors, including p53 [ 519 , 520 ], TDP-43 [ 521 , 522 ], and FUS [ 523 ], containing IDRs that form condensates to compartmentalize and assemble necessary factors [ 6 , 524 ]. Transcription is essentially a nonequilibrium process that employs RNA products to provide a two-way dynamic feedback control in the regulation of electrostatic interactions in transcriptional condensates [ 108 , 525 , 526 ] where RNA products recruit proteins to form molecular scaffolds driving phase separation, whereas many essential RNA processes such as transcription, transport, and metabolism are regulated by phase separation [ 527 ].…”

Section: Melatonin May Attenuate the Stress-induced Aggregation Of Pathological Mlos Via Post-translational Modification And Rna Modificamentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

View full text Add to dashboard Cite

Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

show abstract

TDP-43 regulates transcription at protein-coding genes and Alu retrotransposons

Cited by 23 publications

References 68 publications

Factors Regulating the Activity of LINE1 Retrotransposons

Factors Regulating the Activity of LINE1 Retrotransposons

TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Contact Info

Product

Resources

About