Disrupting pathologic phase transitions in neurodegeneration

Hurtle, Bryan T.; Xie, L. Y.; Donnelly, Christopher J.

doi:10.1172/jci168549

Cited by 17 publications

(6 citation statements)

References 258 publications

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“…The study by Hurtle et al (2023) demonstrated that magnetic, metal, and metalloid NPs have the capacity to disrupt the highly coordinated process of liquid-liquid phase protein separation, thereby giving rise to unique and disease-specific biochemical protein signatures and abnormal protein depositions starting in childhood. As pointed out by Hurtle et al (2023) examining biomolecular phase transitions will help our understanding of the molecular mechanisms mediating toxicity across diverse neurodegenerative diseases with NPs as a common denominator (Kovacs et al, 2013;González-Maciel et al, 2017;Calderón-Garcidueñas et al, 2018, 2019cWennberg et al, 2019;Karanth et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress

Calderón-Garcidueñas,

Stommel,

Torres-Jardón

et al. 2024

Front. Hum. Neurosci.

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The neuropathological hallmarks of Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults—surrogates for children in polluted areas around the world—exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?

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Section: Discussionmentioning

confidence: 99%

Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress

Calderón-Garcidueñas,

Stommel,

Torres-Jardón

et al. 2024

Front. Hum. Neurosci.

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“…S2). The process of LLPS in prion-like RNA-binding proteins (RBPs), including Tau, is differentially influenced by the type of RNA [33][34][35][36], suggesting that the specific domain of RBPs to which the RNA binds and the characteristics of the RNA, such as length and structure, rather than the binding affinity of the RNA, intricately affect Tau LLPS [35]. For example, fused in sarcoma (FUS), a representative amyotrophic lateral sclerosis (ALS)-linked RBP, undergoes a liquid-to-solid phase transition by adding rG4, but not randomized RNAs [37].…”

Section: Discussionmentioning

confidence: 99%

RNA G-quadruplexes and calcium ions synergistically induce Tau phase transitionin vitro

Yabuki,

Matsuo,

Komiya

et al. 2024

Preprint

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Tau aggregation is a defining feature of neurodegenerative tauopathies, including Alzheimer’s disease, corticobasal degeneration, and frontotemporal dementia. This aggregation involves the liquid–liquid phase separation (LLPS) of Tau, followed by its sol–gel phase transition, representing a crucial step in aggregate formation bothin vitroandin vivo. However, the precise cofactors influencing Tau phase transition and aggregation under physiological conditions (e.g., ion concentration and temperature) remain unclear. In this study, we unveil that nucleic acid secondary structures, specifically RNA G-quadruplexes (rG4s), and calcium ions (Ca2+) synergistically facilitated the sol–gel phase transition of human Tau under mimic intracellular ion conditions (140 mM KCl, 15 mM NaCl, and 10 mM MgCl2) at 37□in vitro. In the presence of molecular crowding reagents, Tau formed stable liquid droplets through LLPS, maintaining fluidity for 24 h under physiological conditions. Notably, cell-derived RNA promoted Tau sol–gel phase transition, with G4-forming RNA emerging as a crucial factor. Surprisingly, polyanion heparin did not elicit a similar response, indicating a distinct mechanism not rooted in electrostatic interactions. Further exploration underscored the significance of Ca2+, which accumulate intracellularly during neurodegeneration, as additional cofactors in promoting Tau phase transition after 24 h. Importantly, our findings demonstrate that rG4s and Ca2+synergistically enhance Tau phase transition within 1 h when introduced to Tau droplets. In conclusion, our study illuminates the pivotal roles of rG4s and Ca2+in promoting Tau aggregation under physiological conditionsin vitro, offering insights into potential triggers for tauopathy.

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“…LLPS has emerged as a crucial mechanism in numerous cellular processes, encompassing transcription, protein synthesis, signal transduction and DNA repair. Additionally, LLPS has been implicated in the pathogenesis of various diseases, including neurological disorders ( 52 ). However, whether the formation of liquid condensates is the cause or the result of the mentioned physiological functions remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres

Lee,

Kim,

Park

et al. 2024

Nucleic Acids Research

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Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid–liquid phase separation (LLPS) and the assembly of Alternative Lengthening of Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption of R-loops abolishes LLPS and impairs telomere synthesis. Artificial engineering of telomeric LLPS restores telomere synthesis, underscoring the critical role of LLPS in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading to tri-methylation of Lys27 on histone H3 (H3K27me3) at telomeres. Half of paraffin-embedded tissue sections from human breast cancers exhibit APBs and telomere length heterogeneity, suggesting that BRCA2 mutations can predispose individuals to ALT-type tumorigenesis. Overall, BRCA2 abrogation disrupts the dynamicity of telomeric G4, producing TERRA-R-loops, finally leading to the assembly of telomeric liquid condensates crucial for ALT. We propose that modulating the dynamicity of telomeric G4 and targeting TERRA-R-loops in telomeric LLPS maintenance may represent effective therapeutic strategies for treating ALT-like cancers with APBs, including those with BRCA2 disruptions.

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Disrupting pathologic phase transitions in neurodegeneration

Cited by 17 publications

References 258 publications

RNA G-quadruplexes and calcium ions synergistically induce Tau phase transitionin vitro

Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres

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