Mutations in RNA-binding proteins (RBPs) localized in ribonucleoprotein (RNP) granules, such as hnRNP A1 and TDP-43, promote aberrant protein aggregation, which is a pathological hallmark of various ...neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Protein posttranslational modifications (PTMs) are known to regulate RNP granules. In this study, we investigate the function of poly(ADP-ribosyl)ation (PARylation), an important PTM involved in DNA damage repair and cell death, in RNP granule-related neurodegeneration. We reveal that PARylation levels are a major regulator of the assembly-disassembly dynamics of RNP granules containing disease-related RBPs, hnRNP A1 and TDP-43. We find that hnRNP A1 can both be PARylated and bind to PARylated proteins or poly(ADP-ribose) (PAR). We further uncover that PARylation of hnRNP A1 at K298 controls its nucleocytoplasmic transport, whereas PAR-binding via the PAR-binding motif (PBM) of hnRNP A1 regulates its association with stress granules. Moreover, we reveal that PAR not only dramatically enhances the liquid-liquid phase separation of hnRNP A1, but also promotes the co-phase separation of hnRNP A1 and TDP-43 in vitro and their interaction in vivo. Finally, both genetic and pharmacological inhibition of PARP mitigates hnRNP A1- and TDP-43-mediated neurotoxicity in cell and Drosophila models of ALS. Together, our findings suggest a novel and crucial role for PARylation in regulating the dynamics of RNP granules, and that dysregulation in PARylation and PAR levels may contribute to ALS disease pathogenesis by promoting protein aggregation.
Summary
To elucidate the nature and extent of the lithospheric modification in the central and western North China Craton (NCC) and adjacent regions, we used the wave equation–based migration ...technique of S-receiver function on teleseismic data collected from 314 broadband stations in this region to image the lithospheric structure. Incorporating data from previous lithospheric structure studies, we obtained unprecedented high-resolution depth maps of the lithosphere–asthenosphere boundary (LAB) and mid-lithospheric discontinuity (MLD) in the NCC. Our results show more detailed variations of the lithospheric thickness in the central and western NCC and adjacent regions, which ranges from 100 to >170 km, in marked contrast to the thinned lithosphere (60–100 km) in the eastern NCC. Despite its generally thick lithosphere (>130 km), the Ordos Block shows a concordant N–S difference from the surface to deep lithosphere with a boundary at the latitude of 37–38°N. The central NCC is laterally heterogeneous in the lithospheric structure, and the thick lithosphere (∼160 km) in the south is interpreted as a remnant cratonic mantle root. The central Qinling Orogenic Belt preserves a thick lithosphere (∼150 km), which may block the asthenospheric flow driven by extrusion of the Tibetan Plateau to the west of the NCC. Moreover, a negative MLD is widely identified at the depth of 80–110 km within the thick lithosphere, which corroborates the global existence of the MLD in continental regions. The consistence in the depth of the MLD and the shallow LAB in the eastern NCC supports the conjecture that the MLD may have played an important role in the lithospheric modification of the eastern NCC.
α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different ...α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson's disease (fPD).
In order to analyze proteins, shotgun/bottom-up proteomics was employed, and several techniques related to shotgun proteomics are detailed. This process analyzes proteins by examining the peptides ...released from the protein through proteolysis.
A plethora of software suites and multiple classes of spectral libraries have been developed to enhance the depth and robustness of data-independent acquisition (DIA) data processing. However, how ...the combination of a DIA software tool and a spectral library impacts the outcome of DIA proteomics and phosphoproteomics data analysis has been rarely investigated using benchmark data that mimics biological complexity. In this study, we create DIA benchmark data sets simulating the regulation of thousands of proteins in a complex background, which are collected on both an Orbitrap and a timsTOF instruments. We evaluate four commonly used software suites (DIA-NN, Spectronaut, MaxDIA and Skyline) combined with seven different spectral libraries in global proteome analysis. Moreover, we assess their performances in analyzing phosphopeptide standards and TNF-α-induced phosphoproteome regulation. Our study provides a practical guidance on how to construct a robust data analysis pipeline for different proteomics studies implementing the DIA technique.
Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging remains to be understood. H3K27me3, a highly conserved histone modification ...signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using
, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. We show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 is one of the molecular mechanisms that contribute to aging and that stimulation of glycolysis promotes metabolic health and longevity.
Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL ...promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation.
Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine ...implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS.
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•Caspase-8 activation is defective in pathological samples from MS patients•Insoluble aggregates of RIPK1 and RIPK3 form in human MS cortical lesions•The RIPK1 kinase inhibitor 7N-1 blocks demyelination induced by cuprizone and EAE
Using both animal models and human tissue, Ofengeim et al. provide evidence for the involvement of RIPK1 and necroptosis in mediating the deleterious processes in multiple sclerosis (MS) and provide a link between this disease and other neurodegenerative diseases.
Imaging the crustal structure and state of the Himalayan Orogenic Belt (HOB) is of great significance for understanding crustal deformation and its tectonic response in the collision front of the ...Indian‐Eurasian plates. To avoid the influence from the anomalies underneath the north‐south trending rifts, a three‐dimensional electrical resistivity model across the central HOB was obtained between the Dingjie‐Shenzha and Yadong‐Gulu rifts. No lower‐crustal conductor was found in the southern Lhasa Terrane, and the lower crust with a moderate resistivity value of approximately 100 Ωm is interpreted to be the residue of previous partial melting beneath the Gangdese porphyry copper deposits. The middle crust between the Main Himalayan Thrust and Southern Tibet Detachment System is electrically resistive to the north of the north Himalayan gneiss domes (NHGD) belt and conductive to the south. The middle crust in the northern Himalayas may have undergone partial melting and crystallization during southward migration and duplexing. There is a strong deep‐shallow coupling relationship in the central HOB, where an increase in the underthrusting angle of the Indian crust has resulted in a southward turn of the NHGD belt.
Plain Language Summary
The Himalayan Orogenic Belt (HOB) is an ideal place to study the deep‐shallow coupling relationship of the continental collision system. Magnetotelluric sounding (MT) is a powerful tool for detecting the internal structure and state of collision zones. However, most of the previous results have been overprinted by north–south trending rifts. Therefore, a high‐resolution three‐dimensional electrical resistivity model was obtained across the central HOB through an MT profile between the Dingjie‐Shenzha and Yadong‐Gulu rifts, combined with the latest MT result from the Sikkim region. The electrical resistivity model revealed that the lower crust of the southern Lhasa Terrane is characterized by a moderate resistivity value of approximately 100 Ωm; this may have provided the magma source for the porphyry copper deposits in the eastern Gangdese metallogenic belt and the southward thermal migration in the northern Himalayas. The middle crust of the northern Himalayas is electrically discontinuous toward the south, mainly exhibiting high resistivity north of the north Himalayan gneiss domes (NHGD) belt. The middle crust of the northern Himalayas may have undergone partial melting and crystallization during southward uplift and migration. We found a strong coupling relationship between the surface NHGD belt and the underthrusting of the Indian crust.
Key Points
A three‐dimensional electrical resistivity model was obtained across the central HOB between the Dingjie‐Shenzha and Yadong‐Gulu rifts
A moderate resistivity value in the lower crust of the southern Lhasa Terrane may represent the residue of previous partial melting
The middle crust in the northern Himalayas is electrically discontinuous
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