RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds

Zwierzchowski-Zarate, Amy; Mendoza-Oliva, Ayde; Kashmer, Omar M.; Collazo-Lopez, Josue E; White, Charles L.; Diamond, Marc I.

doi:10.1016/j.jbc.2022.102132

Cited by 23 publications

(33 citation statements)

References 73 publications

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“…Under normal non-disease conditions, tau is largely disordered 20 and is rather resistant to aggregation. Aggregation studies with recombinant tau are facilitated by inducers such as heparin, RNA, or other polyanions 21,22 . While in cell or animal models, recombinant or patient-derived fibrils (i.e., seeds) are required to induce aggregation.…”

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confidence: 99%

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

et al. 2023

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Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

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confidence: 99%

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

et al. 2023

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“…The most well-known biomarkers related to AD are the increase in the levels of beta-amyloid peptide (Aβ), total tau (t-tau), and phospho-tau (p-tau) in cerebrospinal fluid (CSF). Multiple hypotheses have been suggested regarding the pathology of AD, such as the tau hypothesis in which β-amyloid plaques are involved [ 66 ]. The neuroprotective function of reactive astrocytes is mediated by regulating the Amyloid ß-linked (Aβ-linked) neural injury, degradation, and Aβ metabolism, hence, generating a protective barrier against Aβ deposits [ 67 ].…”

Section: Alzheimer’s Diseasementioning

confidence: 99%

Bioactive Compounds of the Mediterranean Diet as Nutritional Support to Fight Neurodegenerative Disease

Franco

Interdonato

Cordaro

et al. 2023

IJMS

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Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress, and neuronal depletion. They include selective malfunction and progressive loss of neurons, glial cells, and neural networks in the brain and spinal cord. There is an urgent need to develop new and more effective therapeutic strategies to combat these devastating diseases because, today, there is no treatment that can cure degenerative diseases; however, we have many symptomatic treatments. Current nutritional approaches are beginning to reflect a fundamental change in our understanding of health. The Mediterranean diet may have a protective effect on the neurodegenerative process because it is rich in antioxidants, fiber, and omega-3 polyunsaturated fatty acids. Increasing knowledge regarding the impact of diet on regulation at the genetic and molecular levels is changing the way we consider the role of nutrition, resulting in new dietary strategies. Natural products, thanks to their bioactive compounds, have recently undergone extensive exploration and study for their therapeutic potential for a variety of diseases. Targeting simultaneous multiple mechanisms of action and a neuroprotection approach with the diet could prevent cell death and restore function to damaged neurons. For these reasons, this review will be focused on the therapeutic potential of natural products and the associations between the Mediterranean-style diet (MD), neurodegenerative diseases, and markers and mechanisms of neurodegeneration.

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“…These polyanionic cofactors have been shown to be critical to the fibril integrity, with spontaneous depolymerisation and monomer release upon cofactor removal [2] . However, the exact nature of the cofactors incorporated into the mature fibril is still poorly understood, with debate surrounding the role of these cofactors in the formation of pathogenic species as well as their localisation in the mature fibrils [5–9] . RNA is of particular interest as it was shown to colocalize with tau fibrils in AD [10] and to trigger formation of tau fibrils with pathogenic behaviour [5,7,8] .…”

Section: Figurementioning

confidence: 99%

Chemical Imaging of RNA‐Tau Amyloid Fibrils at the Nanoscale Using Tip‐Enhanced Raman Spectroscopy

Cooney,

Talaga,

Ury‐Thiery

et al. 2023

Angew Chem Int Ed

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In the presence of cofactors, tau protein can form amyloid deposits in the brain which are implicated in many neurodegenerative disorders. Heparin, lipids, and RNA are used to recreate tau aggregates in vitro from recombinant protein. However, the mechanism of interaction of these cofactors and the interactions between cofactors and tau are poorly understood. Herein, we use tip‐enhanced Raman spectroscopy (TERS) to visualize the spatial distribution of adenine, protein secondary structure, and amino acids (arginine, lysine and histidine) in single polyadenosine (polyA)‐induced tau fibrils with nanoscale spatial resolution (<10–20 nm). Based on reference unenhanced and surface‐enhanced Raman spectra, we show that the polyA anionic cofactor is incorporated in the fibril structure and seems to be superficial to the β‐sheet core, but nonetheless enveloped within the random‐coiled fuzzy coat. TERS images also prove the colocalization of positively charged arginine, lysine, and histidine amino acids and negatively charged polyA, which constitutes an important step forward to better comprehend the action of RNA cofactors in the mechanism of formation of toxic tau fibrils. TERS appears as a powerful technique for the identification of cofactors in individual tau fibrils and their mode of interaction.

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RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds

Cited by 23 publications

References 73 publications

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Bioactive Compounds of the Mediterranean Diet as Nutritional Support to Fight Neurodegenerative Disease

Chemical Imaging of RNA‐Tau Amyloid Fibrils at the Nanoscale Using Tip‐Enhanced Raman Spectroscopy

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