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Physical Chemistry Chemical Physics :... Jul 2024The hallmark of amyloidosis, such as Alzheimer's disease and Parkinson's disease, is the deposition of amyloid fibrils in various internal organs. The onset of the...
The hallmark of amyloidosis, such as Alzheimer's disease and Parkinson's disease, is the deposition of amyloid fibrils in various internal organs. The onset of the disease is related to the strength of cytotoxicity caused by toxic amyloid species. Furthermore, amyloid fibrils show polymorphism, where some types of fibrils are cytotoxic while others are not. It is thus essential to understand the molecular mechanism of cytotoxicity, part of which is caused by the interaction between amyloid polymorphic fibrils and cell membranes. Here, using amyloid polymorphs of hen egg white lysozyme, which is associated with hereditary systemic amyloidosis, showing different levels of cytotoxicity and liposomes of DMPC and DMPG, changes in the secondary structure of the polymorphs and the structural state of phospholipid membranes caused by the interaction were investigated using vacuum-ultraviolet circular dichroism (VUVCD) and Laurdan fluorescence measurements, respectively. Analysis has shown that the more cytotoxic polymorph increases the antiparallel β-sheet content and causes more disorder in the membrane structure while the other less cytotoxic polymorph shows the opposite structural changes and causes less structural disorder in the membrane. These results suggest a close correlation between the structural properties of amyloid fibrils and the degree of structural disorder of phospholipid membranes, both of which are involved in the fundamental process leading to amyloid cytotoxicity.
PubMed: 38952218
DOI: 10.1039/d4cp00965g -
Journal of Biophotonics Jul 2024Neurological disorders such as Parkinson's disease (PD) often adversely affect the vascular system, leading to alterations in blood flow patterns. Functional...
Neurological disorders such as Parkinson's disease (PD) often adversely affect the vascular system, leading to alterations in blood flow patterns. Functional near-infrared spectroscopy (fNIRS) is used to monitor hemodynamic changes via signal measurement. This study investigated the potential of using resting-state fNIRS data through a convolutional neural network (CNN) to evaluate PD with orthostatic hypotension. The CNN demonstrated significant efficacy in analyzing fNIRS data, and it outperformed the other machine learning methods. The results indicate that judicious input data selection can enhance accuracy by over 85%, while including the correlation matrix as an input further improves the accuracy to more than 90%. This study underscores the promising role of CNN-based fNIRS data analysis in the diagnosis and management of the PD. This approach enhances diagnostic accuracy, particularly in resting-state conditions, and can reduce the discomfort and risks associated with current diagnostic methods, such as the head-up tilt test.
PubMed: 38952169
DOI: 10.1002/jbio.202400138 -
Annals of Clinical and Translational... Jul 2024Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this...
Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this retrospective study, we analyzed a cohort of Parkinson's disease patients treated with dopamine agonists and investigated the influence of the dopamine D4 receptor gene polymorphism, DRD4 7R+, which is linked to psychiatric disorders, impulsive traits, and addictive behaviors. We found that DRD4 7R+ is a significant genetic risk factor associated with the severity of ICD.
PubMed: 38952083
DOI: 10.1002/acn3.52111 -
BMC Neurology Jul 2024Dyspnea is considered a silent threat to people diagnosed with Parkinson's disease and may be a common concern in patients, however, little is known about how it affects...
BACKGROUND
Dyspnea is considered a silent threat to people diagnosed with Parkinson's disease and may be a common concern in patients, however, little is known about how it affects quality of life. This study explored the experiences of independently mobile people who are affected by dyspnea in daily life.
METHODOLOGY
This was a cross-sectional mixed methods study that included an online questionnaire and semi-structured interviews. The participants were included if they were diagnosed with Parkinson's disease; had a self-reported Hoehn and Yahr Score I, II or III; were mobilizing independently; and were Arabic speakers. Participants were excluded if they had any other musculoskeletal, cardiac, respiratory, or neurological diseases; or were previous or current smokers; or had been previously hospitalized due to respiratory complications.
RESULTS
A total of 117 participants completed the Arabic version of the Dyspnea-12 Questionnaire. Dyspnea was reported in all participants and that it had an adverse effect on their quality of life, especially during activities of daily living. Additionally, participants reported a lack of knowledge about pulmonary rehabilitation and were unaware of the availability and potential benefits of participation in programs.
CONCLUSION
Dyspnea was reported in people in the early stages (Hoehn and Yahr Stages I, II, and III) of Parkinson's disease, and may benefit from routine assessment of lung function, dyspnea management and participation in pulmonary rehabilitation.
Topics: Humans; Parkinson Disease; Dyspnea; Male; Female; Cross-Sectional Studies; Aged; Middle Aged; Quality of Life; Surveys and Questionnaires; Activities of Daily Living; Aged, 80 and over
PubMed: 38951752
DOI: 10.1186/s12883-024-03608-0 -
Nature Cell Biology Jul 2024α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson's disease and Lewy body dementia, undergoes protein phase separation....
α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson's disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology.
PubMed: 38951707
DOI: 10.1038/s41556-024-01451-6 -
Nature Cell Biology Jul 2024α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and...
α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn's function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson's disease.
PubMed: 38951706
DOI: 10.1038/s41556-024-01456-1 -
Communications Chemistry Jun 2024The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as...
The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.
PubMed: 38951694
DOI: 10.1038/s42004-024-01224-0 -
NPJ Parkinson's Disease Jun 2024Idiopathic rapid eye movement sleep behaviour disorder (iRBD)-a Parkinson's disease (PD) prodrome-might exhibit neural changes similar to those in PD. Substantia nigra...
Idiopathic rapid eye movement sleep behaviour disorder (iRBD)-a Parkinson's disease (PD) prodrome-might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1-the earliest-degenerating dopaminergic neurons in PD-and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson's Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (p < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.
PubMed: 38951528
DOI: 10.1038/s41531-024-00731-0 -
NPJ Parkinson's Disease Jun 2024Many studies have reported metabolomic analysis of different bio-specimens from Parkinson's disease (PD) patients. However, inconsistencies in reported metabolite...
Many studies have reported metabolomic analysis of different bio-specimens from Parkinson's disease (PD) patients. However, inconsistencies in reported metabolite concentration changes make it difficult to draw conclusions as to the role of metabolism in the occurrence or development of Parkinson's disease. We reviewed the literature on metabolomic analysis of PD patients. From 74 studies that passed quality control metrics, 928 metabolites were identified with significant changes in PD patients, but only 190 were replicated with the same changes in more than one study. Of these metabolites, 60 exclusively increased, such as 3-methoxytyrosine and glycine, 54 exclusively decreased, such as pantothenic acid and caffeine, and 76 inconsistently changed in concentration in PD versus control subjects, such as ornithine and tyrosine. A genome-scale metabolic model of PD and corresponding metabolic map linking most of the replicated metabolites enabled a better understanding of the dysfunctional pathways of PD and the prediction of additional potential metabolic markers from pathways with consistent metabolite changes to target in future studies.
PubMed: 38951523
DOI: 10.1038/s41531-024-00732-z -
Dysphagia Jun 2024Around 80% of persons with Parkinson's disease (PD) present symptoms of dysphagia. Although cognitive impairment may contribute to dysphagia, few studies have...
Around 80% of persons with Parkinson's disease (PD) present symptoms of dysphagia. Although cognitive impairment may contribute to dysphagia, few studies have investigated the association between the PD neuropsychological profile and objective measures of swallowing dysfunction. Since the swallowing function comprises involuntary but also voluntary actions, we hypothesize that specific measures of attention and executive functions can be underlined in PD-related dysphagia. Therefore, the aim of this study was to extensively investigate the correlation and the relationship between attentive and executive functions and safety/efficiency of pharyngeal phase of swallowing in people with PD. All participants received a fiberoptic endoscopic evaluation of swallowing and were evaluated using the Penetration Aspiration Scale (PAS); the Yale Pharyngeal Residue Severity Rating Scale (IT-YPRSRS), and the Functional Oral Intake Scale (FOIS-IT). Participants also underwent a neuropsychological assessment covering global cognitive status, attention, and frontal executive functions. Correlations and associations between neuropsychological measures and swallowing components were calculated. Twenty-one participants with PD (mean age 69.38 ± 6.58 years, mean disease duration 8.38 ± 5.31 years; mean MDS-UPDRS III 43.95 ± 24.18) completed all evaluations. The most significant correlations were found between attentive functions (i.e., Stroop Time), and executive functions (i.e., Raven's Progressive Matrices, Digit Backward and Semantic Fluency), and FOIS-IT, PAS, and IT-YPRSRS sinuses and valleculae. These associations were not influenced by disease duration. These results suggest that a dysfunction to attentional processes and/or to executive functions can contribute to penetration and the presence of pharyngeal residue in participants with middle-stage PD.
PubMed: 38951235
DOI: 10.1007/s00455-024-10728-9