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ACS Omega Jun 2024The development of positron emission tomography (PET) tracers capable of detecting α-synuclein (α-syn) aggregates in vivo would represent a breakthrough for advancing...
The development of positron emission tomography (PET) tracers capable of detecting α-synuclein (α-syn) aggregates in vivo would represent a breakthrough for advancing the understanding and enabling the early diagnosis of Parkinson's disease and related disorders. It also holds the potential to assess the efficacy of therapeutic interventions. However, this remains challenging due to different structures of α-syn aggregates, the need for selectivity over other structurally similar amyloid proteins, like amyloid-β (Aβ), which frequently coexist with α-syn pathology, and the low abundance of the target in the brain that requires the development of a high-affinity ligand. To develop a successful PET tracer for the central nervous system (CNS), stringent criteria in terms of polarity and molecular size must also be considered, as the tracer must penetrate the blood-brain barrier and have low nonspecific binding to brain tissue. Here, we report a series of arylpyrazolethiazole (APT) derivatives, rationally designed from a structure-activity relationship study centered on existing ligands for α-syn fibrils, with a particular focus on the selectivity toward α-syn fibrils and control of physicochemical properties suitable for a CNS PET tracer. In vitro competition binding assays performed against [H]MODAG-001 using recombinant α-syn and Aβ fibrils revealed with an inhibition constant of 27.8 ± 9.7 nM and a selectivity of more than 3.3 fold over Aβ. Radiolabeled [C] demonstrated excellent brain penetration in healthy mice with a peak standardized uptake value of 1.94 ± 0.29 and fast washout from the brain ( = 9 ± 1 min). This study highlights the potential of as a lead compound for developing PET tracers to detect α-syn aggregates in vivo.
PubMed: 38882134
DOI: 10.1021/acsomega.4c01301 -
Nature Communications Jun 2024Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in...
Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
Topics: Humans; alpha-Synuclein; Disease Progression; Lewy Body Disease; Aged; Male; Female; Lewy Bodies; Aged, 80 and over; Alzheimer Disease; Brain; Brain Stem; Olfactory Bulb; Middle Aged
PubMed: 38879548
DOI: 10.1038/s41467-024-49402-x -
Microbiology Spectrum Jun 2024The underlying mechanism of thermotolerance, which is a key virulence factor essential for pathogenic fungi such as , is largely unexplored. In this study, our findings...
The underlying mechanism of thermotolerance, which is a key virulence factor essential for pathogenic fungi such as , is largely unexplored. In this study, our findings suggest that Set302, a homolog of Set3 and a subunit of histone deacetylase complex Set3C, contributes to thermotolerance in . Specifically, the deletion of the predicted Set3C core subunit, Set302, resulted in further reduction in the growth of at 39°C, and survival of transient incubation at 50°C. Transcriptomics analysis revealed that the expression levels of numerous heat stress-responsive genes altered at both 30°C and 39°C due to the lack of Set302. Notably, at 39°C, the absence of Set302 led to the downregulation of gene expression related to the ubiquitin-proteasome system (UPS). Based on the GFP-α-synuclein overexpression model to characterize misfolded proteins, we observed a pronounced accumulation of misfolded GFP-α-synuclein at 39°C, consequently inhibiting thermotolerance. Furthermore, the loss of Set302 exacerbated the accumulation of misfolded GFP-α-synuclein during heat stress. Interestingly, the strain exhibited a similar phenotype under proteasome stress as it did at 39°C. Moreover, the absence of Set302 led to reduced production of capsule and melanin. strain also displayed significantly reduced pathogenicity and colonization ability compared to the wild-type strain in the murine infection model. Collectively, our findings suggest that Set302 modulates thermotolerance by affecting the degradation of misfolded proteins and multiple virulence factors to mediate the pathogenicity of .IMPORTANCE is a pathogenic fungus that poses a potential and significant threat to public health. Thermotolerance plays a crucial role in the wide distribution in natural environments and host colonization of this fungus. Herein, Set302, a critical core subunit for the integrity of histone deacetylase complex Set3C and widely distributed in various fungi and mammals, governs thermotolerance and affects survival at extreme temperatures as well as the formation of capsule and melanin in . Additionally, Set302 participates in regulating the expression of multiple genes associated with the ubiquitin-proteasome system (UPS). By eliminating misfolded proteins under heat stress, Set302 significantly contributes to the thermotolerance of . Moreover, Set302 regulates the pathogenicity and colonization ability of in a murine model. Overall, this study provides new insight into the mechanism of thermotolerance in .
PubMed: 38874428
DOI: 10.1128/spectrum.04202-23 -
Frontiers in Aging Neuroscience 2024The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains...
OBJECTIVE
The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction.
METHODS
Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data.
RESULT
Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis.
CONCLUSION
In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.
PubMed: 38872630
DOI: 10.3389/fnagi.2024.1394807 -
Biomedical Reports Jul 2024There is no definite biomarker for confirming the diagnosis of essential tremor (ET) or differentiating it from other diseases, particularly Parkinson's disease. The...
There is no definite biomarker for confirming the diagnosis of essential tremor (ET) or differentiating it from other diseases, particularly Parkinson's disease. The present study aimed to investigate the serum levels of the α-synuclein protein (α-syn) and its autoantibodies in patients with ET compared with healthy controls and its relation to motor and non-motor symptoms in patients with ET. Serum α-syn and its autoantibodies were measured in 32 patients with ET and 32 age- and sex-matched controls. Both groups were assessed using the non-motor symptoms scale, MoCA, Beck Depression Inventory, Hamilton Anxiety Rating Scale, and the Short Form 36 Health Survey Questionnaire. Tremor was assessed using the Fahn-Tolosa-Marin Tremor Rating Scale. The serum α-syn concentration in patients with ET was significantly lower than that in healthy controls (P<0.001), with a positive predictive value of 0.81 and a negative predictive value of 0.75, while the serum anti-a-syn autoantibody concentration was not significantly different between the two groups. There were no correlations between serum α-syn or its autoantibodies and patients' clinical characteristics. Furthermore, patients with ET had worse cognitive impairment, depression, anxiety, non-motor symptoms and quality of life. The serum α-syn concentration was lower in patients with ET than in controls, with favorable predictive values, suggesting that it could serve as a biomarker for ET diagnosis.
PubMed: 38868525
DOI: 10.3892/br.2024.1796 -
EBioMedicine Jun 2024Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However,...
BACKGROUND
Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However, mechanisms by which SARS-CoV-2 disrupts brain function remain unclear and treatment strategies are lacking. We previously demonstrated neuroinflammation in the olfactory bulb of intranasally infected hamsters, followed by alpha-synuclein and tau accumulation in cortex, thus mirroring pathogenesis of neurodegenerative diseases such as Parkinson's or Alzheimer's disease.
METHODS
To uncover the sex-specific spatiotemporal profiles of neuroinflammation and neuronal dysfunction following intranasal SARS-CoV-2 infection, we quantified microglia cell density, alpha-synuclein immunoreactivity and inhibitory interneurons in cortical regions, limbic system and basal ganglia at acute and late post-recovery time points.
FINDINGS
Unexpectedly, microglia cell density and alpha-synuclein immunoreactivity decreased at 6 days post-infection, then rebounded to overt accumulation at 21 days post-infection. This biphasic response was most pronounced in amygdala and striatum, regions affected early in Parkinson's disease. Several brain regions showed altered densities of parvalbumin and calretinin interneurons which are involved in cognition and motor control. Of note, females appeared more affected.
INTERPRETATION
Our results demonstrate that SARS-CoV-2 profoundly disrupts brain homeostasis without neuroinvasion, via neuroinflammatory and protein regulation mechanisms that persist beyond viral clearance. The regional patterns and sex differences are in line with neurological deficits observed after SARS-CoV-2 infection.
FUNDING
Federal Ministry of Health, Germany (BMG; ZMV I 1-2520COR501 to G.G.), Federal Ministry of Education and Research, Germany (BMBF; 03COV06B to G.G.), Ministry of Science and Culture of Lower Saxony in Germany (14-76403-184, to G.G. and F.R.).
PubMed: 38865747
DOI: 10.1016/j.ebiom.2024.105191 -
Journal of Neural Transmission (Vienna,... Jun 2024For a special issue, we review studies on the pathogenesis of nigral cell death and the treatment of sporadic Parkinson's disease (sPD) over the past few decades, with a... (Review)
Review
For a special issue, we review studies on the pathogenesis of nigral cell death and the treatment of sporadic Parkinson's disease (sPD) over the past few decades, with a focus on the studies performed by Prof. Mizuno and our group. Prof. Mizuno proposed the initial concept that mitochondrial function may be impaired in sPD. When working at Jichi Medical School, he found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with Parkinson's disease (PD) and MPTP models. After moving to Juntendo University as a professor and chairman, he continued to study the mechanisms of cell death in the substantia nigra of patients with sPD. Under his supervision, I studied the relationships between PD and apoptosis, PD and iron involvement, mitochondrial dysfunction and apoptosis, and PD and neuroinflammation. Moving to Kitasato University, we focused on PD and the cytotoxicity of alpha synuclein (αSyn) as well as brain neuropathology. Eventually, I moved to Osaka University, where I continued working on PD and αSyn projects to promote therapeutic research. In this paper, we present the details of these studies in the following order: past, present, and future.
Topics: Humans; Parkinson Disease; Animals; Substantia Nigra; alpha-Synuclein
PubMed: 38864935
DOI: 10.1007/s00702-024-02788-w -
Frontiers in Aging Neuroscience 2024Parkinson's disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation,... (Review)
Review
Parkinson's disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood-brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood-brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.
PubMed: 38863783
DOI: 10.3389/fnagi.2024.1345918 -
Brain Communications 2024Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson's disease. Candidate diagnostic tests for Parkinson's disease...
Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson's disease. Candidate diagnostic tests for Parkinson's disease to date have predominantly focused on measurements of α-synuclein in CSF, but there is a need for accurate tests utilizing more easily accessible sample types. Prior studies utilizing saliva have used bulk measurements of salivary α-synuclein to provide diagnostic insight. Aggregate structure may influence the contribution of α-synuclein to disease pathology. Single-molecule approaches can characterize the structure of individual aggregates present in the biofluid and may, therefore, provide greater insight than bulk measurements. We have employed an antibody-based single-molecule pulldown assay to quantify salivary α-synuclein and amyloid-β peptide aggregate numbers and subsequently super-resolved captured aggregates using direct Stochastic Optical Reconstruction Microscopy to describe their morphological features. We show that the salivary α-synuclein aggregate/amyloid-β aggregate ratio is increased almost 2-fold in patients with Parkinson's disease ( = 20) compared with controls ( = 20, < 0.05). Morphological information also provides insight, with saliva from patients with Parkinson's disease containing a greater proportion of larger and more fibrillar amyloid-β aggregates than control saliva ( < 0.05). Furthermore, the combination of count and morphology data provides greater diagnostic value than either measure alone, distinguishing between patients with Parkinson's disease ( = 17) and controls ( = 18) with a high degree of accuracy (area under the curve = 0.87, < 0.001) and a larger dynamic range. We, therefore, demonstrate for the first time the application of highly sensitive single-molecule imaging techniques to saliva. In addition, we show that aggregates present within saliva retain relevant structural information, further expanding the potential utility of saliva-based diagnostic methods.
PubMed: 38863577
DOI: 10.1093/braincomms/fcae178 -
Acta Neuropathologica Communications Jun 2024
PubMed: 38863027
DOI: 10.1186/s40478-024-01789-w