-
Biochemical and Biophysical Research... Jan 2024At the molecular level, aging is often accompanied by dysfunction of stress-induced membrane-less organelles (MLOs) and changes in their physical state (or material...
At the molecular level, aging is often accompanied by dysfunction of stress-induced membrane-less organelles (MLOs) and changes in their physical state (or material properties). In this work, we analyzed the proteins included in the proteome of stress granules (SGs) and P-bodies for their tendency to transform the physical state of these MLOs. Particular attention was paid to the proteins whose gene expression changes during replicative aging. It was shown that the proteome of the studied MLOs consists of intrinsically disordered proteins, 30-40% of which are potentially capable of liquid-liquid phase separation (LLPS). Proteins whose gene expression changes during the transition of human cells to a senescent state make up about 20% of the studied proteomes. There is a statistically significant increase in the number of positively charged proteins in both datasets studied compared to the complete proteomes of these organelles. An increase in the relative content of DNA-, but not RNA-binding proteins, was also found in the SG dataset with senescence-related processes. Among SGs proteins potentially involved in senescent processes, there is an increase in the abundance of potentially amyloidogenic proteins compared to the whole proteome. Proteins common to SGs and P-bodies, potentially involved in processes associated with senescence, form clusters of interacting proteins. The largest cluster is represented by RNA-binding proteins involved in RNA processing and translation regulation. These data indicate that SG proteins, but not proteins of P-bodies, are more likely to transform the physical state of MLOs. Furthermore, these MLOs can participate in processes associated with aging in a coordinated manner.
Topics: Humans; Proteome; Processing Bodies; Stress Granules; Organelles; Computational Biology; Cellular Senescence
PubMed: 38147698
DOI: 10.1016/j.bbrc.2023.149404 -
Acta Neuropathologica Communications Oct 2023Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the...
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies.
Topics: Animals; Humans; Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Drosophila; Frontotemporal Dementia; Motor Neurons; Pick Disease of the Brain; RNA, Messenger; TDP-43 Proteinopathies
PubMed: 37864255
DOI: 10.1186/s40478-023-01656-0 -
Current Topics in Developmental Biology 2024Satellite cells, named for their satellite position around the sarcolemma of the myofibre, are responsible for skeletal muscle regeneration. Satellite cells normally... (Review)
Review
Satellite cells, named for their satellite position around the sarcolemma of the myofibre, are responsible for skeletal muscle regeneration. Satellite cells normally reside in a quiescent state, but rapidly activate the myogenic program and the cell cycle in response to injury. Translational control of gene expression has emerged as an important regulator of satellite cell activity. Quiescent satellite cells maintain low levels of protein synthesis and selectively translate specific mRNAs to conserve limited energy. Activated satellite cells rapidly restore global protein synthesis to meet the demands of proliferating myogenic progenitors that participate in muscle repair. We propose a model by which translational control enables rapid protein level changes in response to injury-induced environmental shifts, serving as both a brake mechanism during quiescence and an accelerator for injury response. In this Chapter, we navigate the processing, translation and metabolism of newly transcribed mRNAs. We review the modifications of mRNA that occur during mRNA processing in the nucleus of satellite cells, and illustrate how these modifications impact the translation and stability of mRNAs. In the cytoplasm, we review how pathways work in concert to regulate protein synthesis globally, while trans acting microRNAs and RNA binding proteins modify specific mRNA translation within a context of tightly regulated protein synthesis. While navigating translational control of gene expression in satellite cells, this chapter reveals that despite significant progress, the field remains nascent in the broader scope of translational control in cell biology. We propose that future investigations will benefit from incorporating emerging global analyses to study translational control of gene expression in rare satellite cells, and we pose unanswered questions that warrant future exploration.
Topics: Satellite Cells, Skeletal Muscle; Animals; Protein Biosynthesis; Humans; Gene Expression Regulation; RNA, Messenger
PubMed: 38670709
DOI: 10.1016/bs.ctdb.2024.02.013 -
Progress in Neurobiology Jan 2024Traditionally, the neural processing of faces and bodies is studied separately, although they are encountered together, as parts of an agent. Despite its social...
Traditionally, the neural processing of faces and bodies is studied separately, although they are encountered together, as parts of an agent. Despite its social importance, it is poorly understood how faces and bodies interact, particularly at the single-neuron level. Here, we examined the interaction between faces and bodies in the macaque inferior temporal (IT) cortex, targeting an fMRI-defined patch. We recorded responses of neurons to monkey images in which the face was in its natural location (natural face-body configuration), or in which the face was mislocated with respect to the upper body (unnatural face-body configuration). On average, the neurons did not respond stronger to the natural face-body configurations compared to the summed responses to their faces and bodies, presented in isolation. However, the neurons responded stronger to the natural compared to the unnatural face-body configurations. This configuration effect was present for face- and monkey-centered images, did not depend on local feature differences between configurations, and was present when the face was replaced by a small object. The face-body interaction rules differed between natural and unnatural configurations. In sum, we show for the first time that single IT neurons process faces and bodies in a configuration-specific manner, preferring natural face-body configurations.
Topics: Animals; Pattern Recognition, Visual; Face; Temporal Lobe; Visual Cortex; Macaca; Brain Mapping
PubMed: 38042248
DOI: 10.1016/j.pneurobio.2023.102545 -
Cell Reports Mar 2024Autophagy and ribonucleoprotein granules, such as P-bodies (PBs) and stress granules, represent vital stress responses to maintain cellular homeostasis. SQSTM1/p62...
Autophagy and ribonucleoprotein granules, such as P-bodies (PBs) and stress granules, represent vital stress responses to maintain cellular homeostasis. SQSTM1/p62 phase-separated droplets are known to play critical roles in selective autophagy; however, it is unknown whether p62 can exist as another form in addition to its autophagic droplets. Here, we found that, under stress conditions, including proteotoxicity, endotoxicity, and oxidation, autophagic p62 droplets are transformed to a type of enlarged PBs, termed p62-dependent P-bodies (pd-PBs). p62 phase separation is essential for the nucleation of pd-PBs. Mechanistically, pd-PBs are triggered by enhanced p62 droplet formation upon stress stimulation through the interactions between p62 and DDX6, a DEAD-box ATPase. Functionally, pd-PBs recruit the NLRP3 inflammasome adaptor ASC to assemble the NLRP3 inflammasome and induce inflammation-associated cytotoxicity. Our study shows that p62 droplet-to-PB transformation acts as a stress response to activate the NLRP3 inflammasome process, suggesting that persistent pd-PBs lead to NLRP3-dependent inflammation toxicity.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Sequestosome-1 Protein; Processing Bodies; Inflammation; Autophagy
PubMed: 38460129
DOI: 10.1016/j.celrep.2024.113935 -
Neurobiology of Disease Jul 2023Distal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some... (Review)
Review
Distal hereditary neuropathies and neuro motor diseases are complex neurological phenotypes associated with pathogenic variants in a large number of genes, but in some the origin is unknown. Recently, rare pathogenic variants of the human VRK1 gene have been associated with these neurological phenotypes. All VRK1 pathogenic variants are recessive, and their clinical presentation occurs in either homozygous or compound heterozygous patients. The pathogenic VRK1 gene pathogenic variants are located in three clusters within the protein sequence. The main, and initial, shared clinical phenotype among VRK1 pathogenic variants is a distal progressive loss of motor and/or sensory function, which includes diseases such as spinal muscular atrophy, Charcot-Marie-Tooth, amyotrophic lateral sclerosis and hereditary spastic paraplegia. In most cases, symptoms start early in infancy, or in utero, and are slowly progressive. Additional neurological symptoms vary among non-related patients, probably because of their different VRK1 variants and their genetic background. The underlying common pathogenic mechanism, by its functional impairment, is a likely consequence of the roles that the VRK1 protein plays in the regulation on the stability and assembly of Cajal bodies, which affect RNA maturation and processing, neuronal migration of RNPs along axons, and DNA-damage responses. Alterations of these processes are associated with several neuro sensory or motor syndromes. The clinical heterogeneity of the neurological phenotypes associated with VRK1 is a likely consequence of the protein complexes in which VRK1 is integrated, which include several proteins known to be associated with Cajal bodies and DNA damage responses. Several hereditary distal neurological diseases are a consequence of pathogenic variants in genes that alter these cellular functions. We conclude that VRK1-related distal hereditary neuropathies and motor neuron diseases represent a novel subgroup of Cajal body related neurological syndromes.
Topics: Humans; Coiled Bodies; Syndrome; Mutation; Motor Neuron Disease; Intracellular Signaling Peptides and Proteins; Charcot-Marie-Tooth Disease
PubMed: 37257665
DOI: 10.1016/j.nbd.2023.106172 -
Signal Transduction and Targeted Therapy Apr 2024RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the...
RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.
Topics: Humans; Autophagy; Colorectal Neoplasms; Family; Phosphoproteins; Proteins; RNA; RNA, Circular; RNA-Binding Proteins
PubMed: 38565536
DOI: 10.1038/s41392-024-01787-3 -
Nature May 2024The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies....
The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies. One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing. What functional role, if any, speckles might play in the process of mRNA splicing is unclear. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.
Topics: Animals; Humans; Male; Mice; Genes; Genome; Human Embryonic Stem Cells; Mouse Embryonic Stem Cells; Nuclear Speckles; RNA Precursors; RNA Splicing; RNA, Messenger; Spliceosomes; Transcription, Genetic
PubMed: 38720076
DOI: 10.1038/s41586-024-07429-6 -
International Journal of Biological... Dec 2023The constitution and forms of rice determine its processing and cooking properties and further control the cooked rice quality. As the two main components, starch and... (Review)
Review
The constitution and forms of rice determine its processing and cooking properties and further control the cooked rice quality. As the two main components, starch and protein content correlations and their characteristics have been extensively explored. However, rice is mainly consumed as polished kernels, components distribution, cytoplasmic matrix, and cell walls work together, and the properties of extracted components or flour are difficult to reflect the quality of cooked rice accurately. Thus, this review summarizes the multi-scale structure changes of main components during real rice cooking conditions. The dynamic thermal changes and leaching behaviors in rice kernels are compared with pure starch or rice flour. The in situ changes and interactions of starch granules, protein bodies, and cell walls during cooking are reviewed. Based on this, different textural evaluation methods are compared, and the advantages and disadvantages are pointed out. The oral chewing perception and bionic chewing simulation for textual evaluation have gradually become hot. Both rice quality controllers and eating quality evaluators attempt to establish an accurate quality evaluation system with the increased demand for high-quality rice.
Topics: Starch; Oryza; Cooking; Cell Wall
PubMed: 37832614
DOI: 10.1016/j.ijbiomac.2023.127403 -
The EMBO Journal Nov 2023RNA turnover regulates the quality and quantity of cellular gene expression through a coordinated cavalcade of enzymes, factors, and phase transitions. In this issue,...
RNA turnover regulates the quality and quantity of cellular gene expression through a coordinated cavalcade of enzymes, factors, and phase transitions. In this issue, Brothers et al reveal the importance of balanced communication between the Xrn1 exonuclease and the EDC4 decapping factor to coordinate P-body dynamics and maintain cellular fitness.
Topics: Processing Bodies; Endoribonucleases; Exoribonucleases; RNA Stability
PubMed: 37750488
DOI: 10.15252/embj.2023115310