Molecular structure of an amyloid fibril formed by FUS low-complexity domain

Sun, Yunpeng; Zhang, Shenqing; Hu, Jiaojiao; Tao, Youqi; Xia, Wencheng; Gu, Jinge; Li, Yichen; Cao, Qing; Li, Dan; Liu, Cong

doi:10.1016/j.isci.2021.103701

Cited by 25 publications

(59 citation statements)

References 60 publications

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“…A single filament allows for the decoration of amyloid cores with regularly spaced globular domains following the helical twist of the fibril, something hardly compatible with a multi-protofilament assembly. Indeed, the fibrils of hnRNPA2 17 and FUS 31 LCDs fused to fluorescent proteins also exhibit a single protofilament, consistent with this being the preferred disposition when globular domains are adjacent to LCDs in the sequence. Instead, the fibrils of hnRNPA1 LCD alone involved two filaments 16 .…”

Section: Hnrnpdl-2 Fibrils Properties Are Reminiscent Of Functional A...mentioning

confidence: 60%

“…To our knowledge, the in vitro cryo-EM hnRNPDL-2 fibrillar structure we report here is the first presented for a full-length RNP, since previous ones were solved departing from the LCD alone 16,29,30 or the LCD fused to a fluorescent protein 17,31 . Thus, we think it should better reflect the in vivo fibrillar packing of this protein family.…”

Section: Hnrnpdl-2 Fibrils Differ From Those Of Other Rnpsmentioning

confidence: 97%

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Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon

García-Pardo¹,

Bartolomé-Nafría²,

Chaves-Sanjuán

et al. 2022

Preprint

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hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing, with missense mutations causing limb-girdle muscular dystrophy-3 (LGMDD3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids, with the RNA binding domains building a solenoidal coat around them. The amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMDD3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs.

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Section: Hnrnpdl-2 Fibrils Properties Are Reminiscent Of Functional A...mentioning

confidence: 60%

Section: Hnrnpdl-2 Fibrils Differ From Those Of Other Rnpsmentioning

confidence: 97%

Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon

García-Pardo¹,

Bartolomé-Nafría²,

Chaves-Sanjuán

et al. 2022

Preprint

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“…Tycko and colleagues first determined the structure of in vitro fibrils obtained from the LCD of FUS by ssNMR, showing that a segment of 61 residues formed the fibril core with a S‐shaped fold and right‐handed twist, which plays a role in LLPS 157 . The following study using a different segment (91 residues) in LCD domain based on cryo‐EM supports for this structural feature by ssNMR 158 (Figure 4B). However, the ex vivo structure of FUS fibrils has not yet been determined.…”

Section: Coaggregation Of Amyloidogenic Proteins With Nucleic Acids I...mentioning

confidence: 87%

Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration

Murakami

Ono

2022

The FASEB Journal

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The aggregation of amyloidogenic proteins is a pathological hallmark of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In these diseases, oligomeric intermediates or toxic aggregates of amyloids cause neuronal damage and degeneration. Despite the substantial effort made over recent decades to implement therapeutic interventions, these neurodegenerative diseases are not yet understood at the molecular level. In many cases, multiple disease-causing amyloids overlap in a sole pathological feature or a sole disease-causing amyloid represents multiple pathological features. Various amyloid pathologies can coexist in the same brain with or without clinical presentation and may even occur in individuals without disease.From sparse data, speculation has arisen regarding the coaggregation of amyloids with disparate amyloid species and other biomolecules, which are the same characteristics that make diagnostics and drug development challenging. However, advances in research related to biomolecular condensates and structural analysis have been used to overcome some of these challenges. Considering the development of these resources and techniques, herein we review the cross-seeding of amyloidosis, for example, involving the amyloids amyloid β, tau, αsynuclein, and human islet amyloid polypeptide, and their cross-inhibition by transthyretin and BRICHOS. The interplay of nucleic acid-binding proteins, such as prions, TAR DNA-binding protein 43, fused in sarcoma/translated in liposarcoma, and fragile X mental retardation polyglycine, with nucleic acids in the pathology of neurodegeneration are also described, and we thereby highlight the potential clinical applications in central nervous system therapy.How to cite this article: Murakami K, Ono K. Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration.

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“…The procedures for protein oligomers negative-staining were established by TEM following our previously described methods with little modification 63,64 . Briefly, 5-10 μl of each sample was dropped on a carbon support membrane, followed by dropwise addition of 5-10 μl of 1% uranyl acetate.…”

Section: Characterisation Of Purified α-Synuclein Aggregationmentioning

confidence: 99%

Cathepsin L-containing exosomes from α-synuclein-activated microglia induce neurotoxicity through the P2X7 receptor

Jiang

Gao

et al. 2022

npj Parkinsons Dis.

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Uncontrolled microglial activation is pivotal to the pathogenesis of Parkinson’s disease (PD), which can secrete Cathepsin L (CTSL) to affect the survival of neurons in the PD patients; however, the precise mechanism has yet to be determined. We demonstrated for the first time that CTSL was mostly released by exosomes derived from α-Syn-activated microglia, resulting in neuronal damage and death. The elevation of CTSL activity was blocked by GW4869, suggesting a critical role for exosomes in mediating CTSL release. Furthermore, the P2X7R/PI3K/AKT signalling pathway was identified as the underlying molecular mechanism since specific antagonists of this signalling pathway, P2X7R knockdown and exosome release inhibitors significantly reduced the injury to cultured mouse cortical neurons. Our study suggests that increased extracellular release of CTSL from α-Syn-activated microglia through exosomes amplifies and aggravates of the neurotoxic effect of microglia, implying that CTSL may be involved in a fresh mechanism of PD pathogenesis, and serve as a potential biomarker and a target for PD drug development.

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Molecular structure of an amyloid fibril formed by FUS low-complexity domain

Cited by 25 publications

References 60 publications

Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon

Cryo-EM Structure of a Mammalian-specific Alternative Amyloid Exon

Interactions of amyloid coaggregates with biomolecules and its relevance to neurodegeneration

Cathepsin L-containing exosomes from α-synuclein-activated microglia induce neurotoxicity through the P2X7 receptor

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