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Molecular Neurodegeneration Jun 2024RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is...
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Brain; Disease Models, Animal; Disease Progression; Frontotemporal Dementia; Mice, Transgenic; Protein Aggregation, Pathological; RNA-Binding Protein FUS
PubMed: 38862967
DOI: 10.1186/s13024-024-00737-5 -
Acta Neuropathologica Communications Jun 2024Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of misfolded α-Synuclein (αSyn) in the brain. These conditions manifest with...
Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of misfolded α-Synuclein (αSyn) in the brain. These conditions manifest with diverse clinical and pathophysiological characteristics. This disease diversity is hypothesized to be driven by αSyn strains with differing biophysical properties, potentially influencing prion-type propagation and consequentially the progression of illness. Previously, we investigated this hypothesis by injecting brain lysate (seeds) from deceased individuals with various synucleinopathies or human recombinant αSyn preformed fibrils (PFFs) into transgenic mice overexpressing either wild type or A53T human αSyn. In the studies herein, we expanded on these experiments, utilizing a panel of antibodies specific for the major carboxyl-terminally truncated forms of αSyn (αSynΔC). These modified forms of αSyn are found enriched in human disease brains to inform on potential strain-specific proteolytic patterns. With monoclonal antibodies specific for human αSyn cleaved at residues 103, 114, 122, 125, and 129, we demonstrate that multiple system atrophy (MSA) seeds and PFFs induce differing neuroanatomical spread of αSyn pathology associated with host specific profiles. Overall, αSyn cleaved at residue 103 was most widely present in the induced pathological inclusions. Furthermore, αSynΔC-positive inclusions were present in astrocytes, but more frequently in activated microglia, with patterns dependent on host and inoculum. These findings support the hypothesis that synucleinopathy heterogeneity might stem from αSyn strains with unique biochemical properties that include proteolytic processing, which could result in dominant strain properties.
Topics: alpha-Synuclein; Animals; Humans; Mice, Transgenic; Mice; Brain; Disease Models, Animal; Synucleinopathies; Antibodies, Monoclonal; Multiple System Atrophy; Prions; Female
PubMed: 38858742
DOI: 10.1186/s40478-024-01805-z -
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 -
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 -
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 -
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 -
Veterinary Immunology and... Jul 2024Influenza A virus (IAV) is a major pathogen in the swine industry. Whole-inactivated virus (WIV) vaccines in swine are highly effective against homologous viruses but...
Influenza A virus (IAV) is a major pathogen in the swine industry. Whole-inactivated virus (WIV) vaccines in swine are highly effective against homologous viruses but provide limited protection to antigenically divergent viruses and may lead to vaccine-associated enhanced respiratory disease (VAERD) after heterologous infection. Although VAERD is reproducible in laboratory studies, clinical diagnosis is challenging, as it would require both knowledge of prior vaccine history and evidence of severe disease by assessment of pathologic lesions at necropsy following infection with a heterologous virus. The objective of this study was to identify potential biomarkers for VAERD for antemortem clinical diagnosis. Naïve pigs were split into two groups, and one group was vaccinated with IAV WIV vaccine. All pigs were then challenged with a heterologous virus to induce VAERD in the vaccinated group and necropsied at 5 days post infection (dpi). Blood was collected on 0, 1, 3, and 5 dpi, and assessed by hematology, plasma chemistry, acute phase proteins, and citrullinated H3 histone (CitH3) assays. Additionally, cytokine and CitH3 levels were assessed in bronchoalveolar lavage fluid (BALF) collected at necropsy. Compared to nonvaccinated challenged pigs, blood collected from vaccinated and challenged (V/C) pigs with VAERD had elevated white blood cells and neutrophils, elevated C-reactive protein and haptoglobin acute phase proteins, and elevated CitH3. In BALF, the proinflammatory cytokine IL-8 and CitH3 were elevated in V/C pigs. In conclusion, a profile of elevated white blood cells and neutrophils, elevated C-reactive protein and haptoglobin, and elevated CitH3 may be relevant for a clinical antemortem IAV VAERD diagnosis.
Topics: Animals; Swine; Orthomyxoviridae Infections; Swine Diseases; Influenza Vaccines; Biomarkers; Influenza A virus; Bronchoalveolar Lavage Fluid; Cytokines; Vaccines, Inactivated
PubMed: 38815504
DOI: 10.1016/j.vetimm.2024.110787 -
The Primary Care Companion For CNS... May 2024
Topics: Humans; Creutzfeldt-Jakob Syndrome; Male; Female; Middle Aged; Aged
PubMed: 38815266
DOI: 10.4088/PCC.23cr03637