USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells

Piatnitskaia, Svetlana; Takahashi, Masahiko; Kitaura, Hiroki; Katsuragi, Yoshihisa; Kakihana, Taichi; Zhang, Lu; Kakita, Akiyoshi; Iwakura, Yuriko; Nawa, Hiroyuki; Miura, Takeshi; Ikeuchi, Takeshi; Hara, Toshifumi; Fujii, Masahiro

doi:10.1038/s41598-019-47033-7

Cited by 35 publications

(29 citation statements)

References 43 publications

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“…Exposing HT22 neuronal cells to stress resulted in the formation of TIA1/Tau-positive stress granules that were severely attenuated by depletion of USP10. In this study, USP10 colocalized with Tau aggregates in the “cell body” of neurons in AD brain lesions suggesting that USP10 is important for stress granule formation in Tau pathology 85 .…”

Section: Usp10 In Alzheimer’s Disease and Other Neurodegenerative Dissupporting

confidence: 54%

When the chains do not break: the role of USP10 in physiology and pathology

et al. 2020

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Deubiquitination is now understood to be as important as its partner ubiquitination for the maintenance of protein half-life, activity, and localization under both normal and pathological conditions. The enzymes that remove ubiquitin from target proteins are called deubiquitinases (DUBs) and they regulate a plethora of cellular processes. DUBs are essential enzymes that maintain intracellular protein homeostasis by recycling ubiquitin. Ubiquitination is a post-translational modification where ubiquitin molecules are added to proteins thus influencing activation, localization, and complex formation. Ubiquitin also acts as a tag for protein degradation, especially by proteasomal or lysosomal degradation systems. With ~100 members, DUBs are a large enzyme family; the ubiquitin-specific peptidases (USPs) being the largest group. USP10, an important member of this family, has enormous significance in diverse cellular processes and many human diseases. In this review, we discuss recent studies that define the roles of USP10 in maintaining cellular function, its involvement in human pathologies, and the molecular mechanisms underlying its association with cancer and neurodegenerative diseases. We also discuss efforts to modulate USPs as therapy in these diseases.

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Section: Usp10 In Alzheimer’s Disease and Other Neurodegenerative Dissupporting

confidence: 54%

When the chains do not break: the role of USP10 in physiology and pathology

et al. 2020

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“…Tau is reported to co‐localize with SG‐associated RBPs, 196 which might lead to the maturation into obstinate pathological SGs during stress. The association of ubiquitin with neurofibrillary tangles is also well documented, 197 in line with shreds of evidence related to Ubiquitin‐specific protease 10 (USP10) as a crucial factor for the formation of SGs comprising tau, TIA‐1, and USP10 198 . USP10 also colocalizes with aggregated tau in AD patients' brain lesions, 198 suggesting its role in SG mediated tau aggregation.…”

Section: Phase Transitions Of Tau In Physiology and Diseasementioning

confidence: 55%

“…The association of ubiquitin with neurofibrillary tangles is also well documented, 197 in line with shreds of evidence related to Ubiquitin‐specific protease 10 (USP10) as a crucial factor for the formation of SGs comprising tau, TIA‐1, and USP10 198 . USP10 also colocalizes with aggregated tau in AD patients' brain lesions, 198 suggesting its role in SG mediated tau aggregation. At the same time, it was found that acetylation decreases the SG‐association of tau 125 .…”

Section: Phase Transitions Of Tau In Physiology and Diseasementioning

confidence: 55%

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

et al. 2021

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Biomolecular condensation via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase‐separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid‐like membrane‐less compartments. However, aberrant phase transitions into gel‐like or solid‐like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule‐associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid‐to‐solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one‐component and complex multi‐component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length‐ and time‐scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.

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“…A relationship between tau and stress granules has been reported (Apicco et al, 2018 ; Piatnitskaia et al, 2019 ) in which T-cell intracellular antigen-1 (TIA-1), a DNA/RNA-binding protein transferred from the nucleus to the cytoplasm during stress may play an important role (Kedersha et al, 2000 ). In fact, TIA-1 co-localizes with pathological tau in human tissue from AD patients (Vanderweyde et al, 2012 ), and a 50% reduction in TIA-1 expression of cytoplasmic stress granules in P301S tau transgenic (PS-19) mice leads to improvements in behavior and lifespan in parallel with reduced neuronal and synaptic degeneration (Apicco et al, 2018 ).…”

Section: New Tau-target Therapy For Tauopathiesmentioning

confidence: 99%

New Insights Into Drug Discovery Targeting Tau Protein

Soeda

Takashima

2020

Front. Mol. Neurosci.

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Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

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USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells

Cited by 35 publications

References 43 publications

When the chains do not break: the role of USP10 in physiology and pathology

When the chains do not break: the role of USP10 in physiology and pathology

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

New Insights Into Drug Discovery Targeting Tau Protein

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