Aging RNA granule dynamics in neurodegeneration

Rhine, Kevin; Al-Azzam, Norah; Chen, Yu; Yeo, G

doi:10.3389/fmolb.2022.991641

Cited by 6 publications

(5 citation statements)

References 132 publications

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“…A recent study identified IP 7 kinase PPIP5K as an α-synuclein neurotoxicity modulator by functional RNAi screening using nematode Perkinson's disease model ( 27 ). Moreover, IP6K and IP 7 facilitate the formation of aberrant protein-RNA aggregates inducing neurotoxicity in various neurodegenerative disorders ( 28 ) at least via promoting the interaction of RNA-binding proteins (for IP6K) and inhibiting the 5′-decapping reaction of non-translated mRNAs (for IP 7 ) ( 29 , 30 ). In addition, IP 7 competitively binds to AKT and inhibits its downstream signaling including mTOR, a key regulator of cell survival ( 31 , 32 ) (Information of proteins associating with IP 6 was summarized in Supplementary Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis

Ito,

Fujii,

Kohara

et al. 2024

Front. Neurol.

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BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state.MethodsWe used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state.ResultsSOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals.ConclusionBy directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.

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Section: Discussionmentioning

confidence: 99%

Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis

Ito,

Fujii,

Kohara

et al. 2024

Front. Neurol.

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“…RBPs such as TDP-43, FUS, and hnRNPA1/A2 are normally localized in the nucleus in a soluble single-state phase, where they bind with RNA and shuttle continuously between the nucleus and cytoplasm [47]. Unfortunately, when RBPs are mislocalized in the cytoplasm, insoluble solid pathological aggregates thus take shape and participate in the formation of stress granules (SGs), as several studies have suggested [83,84]. These aggregates not only impair neuronal homeostasis and disrupt the regulation of nuclear RNA processing but also trigger several dysfunctions, such as mitochondrial dysfunction and inflammation.…”

Section: Rna-binding Protein Llps: Tdp-43 and Fus As Paradigms In Als...mentioning

confidence: 99%

The Role of Liquid‒Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases

Lu,

et al. 2024

Aging and disease

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It is widely accepted that living organisms form highly dynamic membrane-less organelles (MLOS) with various functions through phase separation, and the indispensable role that phase separation plays in the mechanisms of normal physiological functions and pathogenesis is gradually becoming clearer. Pathological aggregates, regarded as hallmarks of neurodegenerative diseases, have been revealed to be closely related to aberrant phase separation. Specific proteins are assembled into condensates and transform into insoluble inclusions through aberrant phase separation, contributing to the development of diseases. In this review, we present an overview of the progress of phase separation research, involving its biological mechanisms and the status of research in neurodegenerative diseases, focusing on five main disease-specific proteins, tau, TDP-43, FUS, α-Syn and HTT, and how exactly these proteins reside within dynamic liquid-like compartments and thus turn into solid deposits. Further studies will yield new perspectives for understanding the aggregation mechanisms and potential therapeutic strategies, and future research directions are anticipated.

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“…We also understand little about how the compositional heterogeneity changes over time within individual condensate entities. For example, stress granules appear to contain distinct subproteomes under different stresses (Aulas et al, 2017;Markmiller et al, 2018) and can mature into solid-or gel-like inclusions that persist within the cell in neurodegenerative diseases (Rhine et al, 2022). At least 238 proteins have been curated to reside in stress granules (Markmiller et al, 2018).…”

Section: Understanding the Origins And Functional Implications Of Het...mentioning

confidence: 99%

Grand challenges in biomolecular condensates: structure, function, and formation

Hatters

2023

Front. Biophys.

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Biomolecular condensates describe concentrated nonstoichiometric assemblies of biomolecules that can form by a range of different mechanisms 1). Biomolecular condensates can arise by phase separation, which in biology involves the demixing of a water-soluble polymer into two co-existing phases: a polymer-dilute phase and a polymer-dense phase. Coacervates describe phase separation mediated by a third element, which may typically be a ligand (such as RNA) to the polymer (such as a protein) that undergoes phase separation. Protein aggregation into amyloids and amorphous aggregates, and the formation of RNA granules, represent other forms of biomolecular condensates. The assembly of proteins and other biomolecules into complexes is a fundamental feature for the execution of biological functions. Biomolecular condensates are a natural variation of the assembly theme. There is an incredible complexity and diversity to how condensates form, are regulated and are structured (reviewed recently in 2)). And there is incredible diversity to how condensates are used by nature to drive biological functions and how when their assemblies go wrong, they can drive disease mechanisms, such as amyloids in neurodegeneration.

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Aging RNA granule dynamics in neurodegeneration

Cited by 6 publications

References 132 publications

Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis

Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis

The Role of Liquid‒Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases

Grand challenges in biomolecular condensates: structure, function, and formation

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