Vulnerability of microRNA biogenesis in FTD–ALS

Eitan, Chen; Hornstein, Eran

doi:10.1016/j.brainres.2015.12.063

Cited by 34 publications

(37 citation statements)

References 90 publications

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“…Roles for EMVs in neurodegenerative disease progression include intercellular communication and neuroinflammation due to transport of parent-cell specific cargo that can be translated in recipient cells and also affect gene regulation [148,149,150]. In Amyotrophic Lateral Sclerosis (ALS), exosomes have for example been shown to export misfolded mutant superoxide dismutase 1 (SOD1) [151,152]; in relation to ALS and Frontotemporal dementia (FTD) to export TAR DNA-binding protein 43 (TDP-43) [153,154]; and there is increasing evidence emerging for critical roles for miRNA transport in the pathogenesis of FTD-ALS [155,156]. In tauopathies, EMVs have been shown to export phosphorylated tau [157,158]; in Parkinson’s disease (PD), exosomes were shown to export α-synuclein and leucine-rich repeat kinase 2 (LRRK2) [159,160,161]; and in Alzheimer’s disease (AD), they export amyloid β (Aβ) [162,163].…”

Section: Emvs In Neurodegenerative Diseasesmentioning

confidence: 99%

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Lange

Gallagher

Kholia

et al. 2017

IJMS

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Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and novel ways for manipulating their release from cells have recently been highlighted. One of the pathways involved in EMV shedding is driven by peptidylarginine deiminase (PAD) mediated post-translational protein deimination, which is calcium-dependent and affects cytoskeletal rearrangement amongst other things. Increased PAD expression is observed in various cancers and neurodegeneration and may contribute to increased EMV shedding and disease progression. Here, we review the roles of PADs and EMVs in cancer and neurodegeneration.

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Section: Emvs In Neurodegenerative Diseasesmentioning

confidence: 99%

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Lange

Gallagher

Kholia

et al. 2017

IJMS

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“…During canonical miRNA biogenesis [109], miRNAs are synthesized from primary miRNAs, which are transcribed in the nucleus. Primary mRNAs are processed into pre-miRNAs by Drosha and subsequently exported to the cytoplasm.…”

Section: Micrornamentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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“…Moreover, misfolded proteins, such as ALS-linked variants of superoxide dismutase 1 (SOD1), can specifically accumulate and aggregate with SGs, which influences their composition and dynamics and triggers an aberrant liquid-tosolid transition (Mateju et al, 2017). Importantly, pathogenic ALScausing mutations in FUS are sufficient to inhibit miRNA biogenesis (Eitan and Hornstein, 2016;Emde et al, 2015).…”

Section: Liquid-like Organelle Formation Through Phase Separationmentioning

confidence: 99%

“…Cellular stresses, such as reactive oxygen species (ROS), phorbol ester and Ras oncogene activation also inhibit Dicer protein expression in several cell types (Wiesen and Tomasi, 2009), and Dicer expression and activity is important for adaptive cellular responses to chronic hypoxic stress (Ho et al, 2012). In addition, upon stress, Dicer and Drosha can directly bind to the LCD proteins TAR DNA-binding protein 43 (TDP43; also known as TARDBP) and FUS in SGs, which affects the efficiency of their function in miRNA processing (Eitan and Hornstein, 2016;Emde et al, 2015;Kawahara and Mieda-Sato, 2012). These data demonstrate that Drosha and Dicer, key components that regulate the first steps of miRNA biogenesis, are controlled by stress, which in turn affects the cellular ability to cope with stress.…”

Section: The Dicer Complexmentioning

confidence: 99%

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

Kucherenko

Shcherbata

2018

Journal of Cell Science

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Stress can be temporary or chronic, and mild or acute. Depending on its extent and severity, cells either alter their metabolism, and adopt a new state, or die. Fluctuations in environmental conditions occur frequently, and such stress disturbs cellular homeostasis, but in general, stresses are reversible and last only a short time. There is increasing evidence that regulation of gene expression in response to temporal stress happens post-transcriptionally in specialized subcellular membrane-less compartments called ribonucleoprotein (RNP) granules. RNP granules assemble through a concentrationdependent liquid-liquid phase separation of RNA-binding proteins that contain low-complexity sequence domains (LCDs). Interestingly, many factors that regulate microRNA (miRNA) biogenesis and alternative splicing are RNA-binding proteins that contain LCDs and localize to stress-induced liquid-like compartments. Consequently, gene silencing through miRNAs and alternative splicing of premRNAs are emerging as crucial post-transcriptional mechanisms that function on a genome-wide scale to regulate the cellular stress response. In this Review, we describe the interplay between these two post-transcriptional processes that occur in liquid-like compartments as an adaptive cellular response to stress.

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Vulnerability of microRNA biogenesis in FTD–ALS

Cited by 34 publications

References 90 publications

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

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