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Biomedicine & Pharmacotherapy =... Jul 2024Ubiquitination is a key mechanism for post-translational protein modification, affecting protein localization, metabolism, degradation and various cellular physiological... (Review)
Review
Ubiquitination is a key mechanism for post-translational protein modification, affecting protein localization, metabolism, degradation and various cellular physiological processes. Dysregulation of ubiquitination is associated with the pathogenesis of various diseases, such as tumors and cardiovascular diseases, making it a primary area of interest in biochemical research and drug development endeavors. E3 ubiquitin ligases play a pivotal role in modulating the ubiquitination of substrate proteins through their unique recognition functions. TRIM31, a member of the TRIM family of E3 ubiquitin ligases, is aberrantly expressed in different pathophysiological conditions. The biological function of TRIM31 is associated with the occurrence and development of diverse diseases. TRIM31 has been demonstrated to inhibit inflammation by promoting ubiquitin-proteasome-mediated degradation of the sensing protein NLRP3 in the inflammasome. TRIM31 mediates ubiquitination of MAVS, inducing the formation of prion-like aggregates, and triggering innate antiviral immune responses. TRIM31 is also implicated in tumor pathophysiology through its ability to promote ubiquitination of the tumor suppressor protein p53. These findings indicate that TRIM31 is a potential therapeutic target, and subsequent in-depth research of TRIM31 is anticipated to provide information on its clinical application in therapy.
Topics: Humans; Ubiquitin-Protein Ligases; Tripartite Motif Proteins; Animals; Ubiquitination; Neoplasms; Molecular Targeted Therapy
PubMed: 38850648
DOI: 10.1016/j.biopha.2024.116846 -
Alzheimer's Research & Therapy Jun 2024Recent reports suggest that amyloid beta (Aβ) peptides can exhibit prion-like pathogenic properties. Transmission of Aβ peptide and the development of associated...
BACKGROUND
Recent reports suggest that amyloid beta (Aβ) peptides can exhibit prion-like pathogenic properties. Transmission of Aβ peptide and the development of associated pathologies after surgeries with contaminated instruments and intravenous or intracerebral inoculations have now been reported across fish, rodents, primates, and humans. This raises a worrying prospect of Aβ peptides also having other characteristics typical of prions, such as evasion of the digestive process. We asked if such transmission of Aβ aggregates via ingestion was possible.
METHODS
We made use of a transgenic Drosophila melanogaster line expressing human Aβ peptide prone to aggregation. Fly larvae were fed to adult zebrafish under two feeding schemes. The first was a short-term, high-intensity scheme over 48 h to determine transmission and retention in the gut. The second, long-term scheme specifically examined retention and accumulation in the brain. The gut and brain tissues were examined by histology, western blotting, and mass spectrometric analyses.
RESULTS
None of the analyses could detect Aβ aggregates in the guts of zebrafish following ingestion, despite being easily detectable in the feed. Additionally, there was no detectable accumulation of Aβ in the brain tissue or development of associated pathologies after prolonged feeding.
CONCLUSIONS
While human Aβ aggregates do not appear to be readily transmissible by ingestion across species, two prospects remain open. First, this mode of transmission, if occurring, may stay below a detectable threshold and may take much longer to manifest. A second possibility is that the human Aβ peptide is not able to trigger self-propagation or aggregation in other species. Either possibility requires further investigation, taking into account the possibility of such transmission from agricultural species used in the food industry.
Topics: Animals; Zebrafish; Amyloid beta-Peptides; Animals, Genetically Modified; Drosophila melanogaster; Brain; Humans; Eating; Larva; Protein Aggregates
PubMed: 38849926
DOI: 10.1186/s13195-024-01487-8 -
Movement Disorders : Official Journal... Jun 2024Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and...
BACKGROUND
Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia.
OBJECTIVE
The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers.
METHODS
Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration.
RESULTS
We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout).
CONCLUSIONS
The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PubMed: 38847384
DOI: 10.1002/mds.29879 -
Neural Regeneration Research Jun 2024PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC), is the infectious prion agent responsible for fatal neurodegenerative diseases of...
PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, posing challenges for the development of effective therapies. Since PrPC is the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity, it represents an attractive therapeutic target for prion diseases. In this minireview, we briefly outline the approaches to target PrPC and discuss our recent identification of Zn(II)-BnPyP, a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action. We argue that in-depth understanding of the molecular mechanism by which Zn(II)-BnPyP targets PrPC may lead toward the development of a new class of dual mechanism anti-prion compounds.
PubMed: 38845221
DOI: 10.4103/NRR.NRR-D-24-00181 -
Bulletin of Mathematical Biology Jun 2024Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress,...
Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress, triggering the Unfolded Protein Response (UPR), which slows or stops protein translation and can indirectly reduce the toxic load. However, the UPR may also trigger processes leading to apoptotic cell death and the UPR is implicated in the progression of several NDs. In this paper, we develop a novel mathematical model to describe the spatiotemporal dynamics of the UPR mechanism for prion diseases. Our model is centered around a single neuron, with representative proteins P (healthy) and S (toxic) interacting with heterodimer dynamics (S interacts with P to form two S's). The model takes the form of a coupled system of nonlinear reaction-diffusion equations with a delayed, nonlinear flux for P (delay from the UPR). Through the delay, we find parameter regimes that exhibit oscillations in the P- and S-protein levels. We find that oscillations are more pronounced when the S-clearance rate and S-diffusivity are small in comparison to the P-clearance rate and P-diffusivity, respectively. The oscillations become more pronounced as delays in initiating the UPR increase. We also consider quasi-realistic clinical parameters to understand how possible drug therapies can alter the course of a prion disease. We find that decreasing the production of P, decreasing the recruitment rate, increasing the diffusivity of S, increasing the UPR S-threshold, and increasing the S clearance rate appear to be the most powerful modifications to reduce the mean UPR intensity and potentially moderate the disease progression.
Topics: Unfolded Protein Response; Prion Diseases; Mathematical Concepts; Neurons; Humans; Models, Neurological; Animals; Nonlinear Dynamics; Computer Simulation; Prions; Spatio-Temporal Analysis; Apoptosis
PubMed: 38837083
DOI: 10.1007/s11538-024-01307-y -
Intractable & Rare Diseases Research May 2024The Japanese Research Group for Neuro-infectious Diseases was founded in August 1996, and by 2004 it had evolved into the Japanese Society for Neuro-infectious Diseases....
The Japanese Research Group for Neuro-infectious Diseases was founded in August 1996, and by 2004 it had evolved into the Japanese Society for Neuro-infectious Diseases. The Society focuses on neuroinfectious conditions (., encephalitis/encephalopathy, myelitis, and meningitis), providing a venue for academic presentations and exchanges. Clinical guidelines for major neurological infectious diseases are also published by the Society, in order to meet the social demands of each era. Although the threat of herpes simplex encephalitis has declined due to acyclovir's introduction, the frequency of encephalitis or peripheral neuropathy caused by varicella-zoster virus is increasing. In Japan, prion disease, human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy (HAM), subacute sclerosing panencephalitis (SSPE), and progressive multifocal leukoencephalopathy (PML) are designated as intractable diseases. The incidence of prion disease is 1.8/1,000,000 individuals, with the sporadic type accounting for 80%. Prion disease is fatal, and effective medications are awaited. HAM's prevalence is ~3/100,000 individuals, with a male-to-female ratio of 1:2-3. HAM is common in western Japan, including Kyushu and Okinawa. The prevalence of PML is rising with the spread of both immunosuppressive therapy for transplantation and treatment for multiple sclerosis. From late 2019 through 2020, the world faced a global outbreak of coronavirus disease 2019 (COVID-19) due to virus mutations, and the threat of new mutations persists. Close attention should be paid to the emergence of new neurological infections that could arise from abnormal weather patterns and/or a decline in immune function due to aging.
PubMed: 38836177
DOI: 10.5582/irdr.2024.01008 -
Neuro-oncology Jun 2024Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM...
Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occur through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that is dependent on Angiopoietin (Ang-2) and vascular endothelial growth factor (VEGF). In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and post-mortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcome were analyzed in BM patients. Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human brain metastases negatively correlated with survival. Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevent the outgrowth of macrometastases.
PubMed: 38831719
DOI: 10.1093/neuonc/noae094 -
Proceedings of the National Academy of... Jun 2024
PubMed: 38830111
DOI: 10.1073/pnas.2408899121 -
Heliyon Jun 2024The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some...
The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, , Contactin-associated protein-like 2 and , prion protein genes. Overall, 27 SNPs were selected by a tagging approach. -rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with and genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.
PubMed: 38828303
DOI: 10.1016/j.heliyon.2024.e31624 -
BioRxiv : the Preprint Server For... May 2024H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple non-human...
H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple non-human mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids, and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine strains. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.
PubMed: 38826368
DOI: 10.1101/2024.05.23.595634