Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules

Andrusiak, Matthew G.; Sharifnia, Panid; Lyu, Xiaohui; Wang, Zhiping; Dickey, Andrea M.; Wu, Zilu; Chisholm, Andrew; Jin, Yishi

doi:10.1016/j.neuron.2019.07.004

Cited by 61 publications

(55 citation statements)

References 92 publications

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“…It involves multivalent molecular interactions mediated by repeated domains as well as low-complexity domains that are prone to interact with both RNA and protein and frequently found in neuronal RBPs (Formicola et al, 2019; Franzmann and Alberti, 2019). Consistent with surface tension dictating their morphology, neuronal RNP granules are spherical at rest and deform under the shear stress induced by fast axonal transport (Gopal et al, 2017; Andrusiak et al, 2019). Furthermore, combining high resolution imaging with FRAP experiments revealed that neuronal RNP granules behave as droplets, undergoing fusion with characteristic relaxation times together with rapid internal rearrangements and constant exchange with the surrounding cytoplasm (Cougot et al, 2008; Park et al, 2014; El Fatimy et al, 2016; Gopal et al, 2017; Andrusiak et al, 2019).…”

Section: Neuronal Rnp Granules Are Membraneless Phase-separated Organmentioning

confidence: 96%

Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

Pushpalatha

Besse

2019

Front. Mol. Biosci.

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Eukaryotic cell compartmentalization relies on long-known membrane-delimited organelles, as well as on more recently discovered membraneless macromolecular condensates. How these two types of organelles interact to regulate cellular functions is still largely unclear. In this review, we highlight how membraneless ribonucleoprotein (RNP) organelles, enriched in RNAs and associated regulatory proteins, cooperate with membrane-bound organelles for tight spatio-temporal control of gene expression in the axons of neuronal cells. Specifically, we present recent evidence that motile membrane-bound organelles are used as vehicles by RNP cargoes, promoting the long-range transport of mRNA molecules to distal axons. As demonstrated by recent work, membrane-bound organelles also promote local protein synthesis, by serving as platforms for the local translation of mRNAs recruited to their outer surface. Furthermore, dynamic and specific association between RNP cargoes and membrane-bound organelles is mediated by bi-partite adapter molecules that interact with both types of organelles selectively, in a regulated-manner. Maintaining such a dynamic interplay is critical, as alterations in this process are linked to neurodegenerative diseases. Together, emerging studies thus point to the coordination of membrane-bound and membraneless organelles as an organizing principle underlying local cellular responses.

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Section: Neuronal Rnp Granules Are Membraneless Phase-separated Organmentioning

confidence: 96%

Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

Pushpalatha

Besse

2019

Front. Mol. Biosci.

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“…Serine/threonine phosphorylation has been shown to promote phase separation of IDPs such as fragile X mental retardation protein (FMRP) [32], TIA-1/TIAL RNA binding protein homolog (TIAR-2) [33], and microtubule-binding protein tau [34]. FMRP has 12 serine residues within its C-terminal IDR (aa 445–632) that have been identified as targets of casein kinase II (CKII).…”

Section: Post-translational Modifications Of Intrinsically Disordementioning

confidence: 99%

“…In vitro phosphorylation by CKII results in an increase in the negative charge densities throughout this IDR, increasing the propensity for multivalent electrostatic interactions and promoting phase separation [32]. TIAR-2 also contains a C-terminal intrinsically disordered PrLD that facilitates its LLPS into cytosolic granules [33]. The PrLD of TIAR-2 was shown to be serine phosphorylated when expressed in mechanosensory neurons.…”

Section: Post-translational Modifications Of Intrinsically Disordementioning

confidence: 99%

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The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins

Owen

Shewmaker

2019

IJMS

177

161

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Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes.

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“…T-cell-restricted intracellular antigen-1 (TIA1) mutations were found to delay stress granule disassembly and to promote the accumulation of granules harboring TDP-43 (Mackenzie et al, 2017). C. elegans TIAR-2/TIA protein functions cell autonomously to inhibit axon regeneration (Andrusiak et al, 2019). One of the important roles of phase separation is transcription enhancement (Sabari et al, 2018), which might be related to local translation/transcription.…”

Section: Interaction Among the Mechanisms Already Describedmentioning

confidence: 99%

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

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Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules

Cited by 61 publications

References 92 publications

Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

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