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Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's...
OBJECTIVE
To investigate the mechanisms that mediate the neuroprotective effect of the intestinal microbial metabolite sodium butyrate (NaB) in a mouse model of Parkinson's disease (PD) the gut-brain axis.
METHODS
Thirty-nine 7-week-old male C57BL/6J mice were randomized equally into control group, PD model group, and NaB treatment group. In the latter two groups, PD models were established by intraperitoneal injection of 30 mg/kg 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) once daily for 5 consecutive days, and normal saline was injected in the control group. After modeling, the mice received daily gavage of NaB (300 mg/kg) or an equal volume of saline for 14 days. Behavioral tests were carried out to assess the changes in motor function of the mice, and Western blotting was performed to detect the expressions of tyrosine hydroxylase (TH) and -synuclein (-syn) in the striatum and nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-), interleukin 6 (IL-6), and the tight junction proteins ZO-1, Occludin, and Claudinin the colon. HE staining was used to observe inflammatory cell infiltration in the colon of the mice. RNA sequencing analysis was performed to identify the differentially expressed genes in mouse colon tissues, and their expressions were verified using qRT-PCR and Western blotting.
RESULTS
The mouse models of PD with NaB treatment showed significantly increased movement speed and pulling strength of the limbs with obviously upregulated expressions of TH, Occludin, and Claudin and downregulated expressions of -syn, NF-κB, TNF-, and IL-6 (all < 0.05). HE staining showed that NaB treatment significantly ameliorated inflammatory cell infiltration in the colon of the PD mice. RNA sequencing suggested that Bmal1 gene probably mediated the neuroprotective effect of NaB in PD mice ( < 0.05).
CONCLUSION
NaB can improve motor dysfunction, reduce dopaminergic neuron loss in the striatum, and ameliorate colonic inflammation in PD mice possibly through a mechanism involving Bmal1.
Topics: Animals; Mice; Butyric Acid; Male; Mice, Inbred C57BL; Neuroprotective Agents; Disease Models, Animal; Parkinson Disease; alpha-Synuclein; Tumor Necrosis Factor-alpha; NF-kappa B; Interleukin-6; Tyrosine 3-Monooxygenase; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Corpus Striatum; Occludin; Brain-Gut Axis
PubMed: 38862445
DOI: 10.12122/j.issn.1673-4254.2024.05.09 -
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 -
MicroPublication Biology 2024Abnormal synaptic aggregation of α-synuclein is linked to cognitive deficits in Parkinson's disease (PD). While the impacts of excess α-synuclein on synaptic function...
Abnormal synaptic aggregation of α-synuclein is linked to cognitive deficits in Parkinson's disease (PD). While the impacts of excess α-synuclein on synaptic function are well established, comparatively less is known about the effects on local mitochondria. Here, we examined morphological features of synaptic mitochondria treated with wild type (WT) or phosphoserine 129 (pS129) α-synuclein, a variant with prominent synaptic accumulation in PD. Acute introduction of pS129 α-synuclein to lamprey synapses caused an activity-dependent swelling and bursting of mitochondria, which did not occur with WT α-synuclein. These pS129-induced effects on mitochondria likely contribute to the synaptic deficits observed in PD.
PubMed: 38854632
DOI: 10.17912/micropub.biology.001206 -
Modern Pathology : An Official Journal... Jun 2024Multiple system atrophy (MSA) is a neurodegenerative disorder with variable disease course and distinct constellations of clinical (cerebellar [MSA-C] or parkinsonism...
Multiple system atrophy (MSA) is a neurodegenerative disorder with variable disease course and distinct constellations of clinical (cerebellar [MSA-C] or parkinsonism [MSA-P]) and pathological phenotypes, suggestive of distinct α-synuclein (αSyn) strains. Neuropathologically, MSA is characterized by the accumulation of αSyn in oligodendrocytic glial cytoplasmic inclusions (GCI). Using a novel computer-based method, this study quantified the size of GCIs, density of all αSyn pathology, density of only the GCIs, and number of GCIs in MSA cases (n = 20). The putamen and cerebellar white matter were immunostained with the disease-associated 5G4 anti-αSyn antibody. Following digital scanning and image processing, total 5G4-immunoreactive pathology (ie, neuronal, neuritic, and glial) and GCIs were optically dissected for inclusion size and density measurement and then evaluated applying a novel computer-based method using ImageJ. GCI size varied between cases and brain regions (P < .0001), and heterogeneity in the density of all αSyn pathology including the density and number of GCIs were observed between regions and across cases, where MSA-C cases had a significantly higher density of all αSyn pathology in the cerebellar white matter (P = .049). Some region-specific morphologic variables inversely correlated with the age of onset and death, suggestive of an underlying aging-related cellular mechanism. Unsupervised K-means cluster analysis classified MSA cases into 3 distinct groups based on region-specific morphologic variables. In conclusion, we developed a novel computer-based method that is easily accessible, providing a first step to developing artificial intelligence-based evaluation strategies for large scale comparative studies. Our observations on the variability of morphologic variables between brain regions and cases highlight (1) the importance of computer-based approaches to detect features not considered in the routine diagnostic practice, and (2) novel aspects for the identification of previously unrecognized MSA subtypes that do not necessarily reflect the current clinical classification of MSA-C or MSA-P.
PubMed: 38852813
DOI: 10.1016/j.modpat.2024.100533 -
Chemical Science Jun 2024Insoluble amyloids rich in cross-β fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct...
Insoluble amyloids rich in cross-β fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloids in a conformationally specific manner are lacking. We introduce a novel computational method for design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aβ40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.
PubMed: 38846390
DOI: 10.1039/d3sc06245g -
Neural Regeneration Research Jun 2024Poststroke cognitive impairment is a major secondary effect of ischemic stroke in many patients; however, few options are available for the early diagnosis and treatment...
Poststroke cognitive impairment is a major secondary effect of ischemic stroke in many patients; however, few options are available for the early diagnosis and treatment of this condition. The aims of this study were to (1) determine the specific relationship between hypoxic and α-synuclein during the occur of poststroke cognitive impairment and (2) assess whether the serum phosphorylated α-synuclein level can be used as a biomarker for poststroke cognitive impairment. We found that the phosphorylated α-synuclein level was significantly increased and showed pathological aggregation around the cerebral infarct area in a mouse model of ischemic stroke. In addition, neuronal α-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia, suggesting that hypoxia is the underlying cause of α-synuclein-mediated pathology in the brains of mice with ischemic stroke. Serum phosphorylated α-synuclein levels in patients with ischemic stroke were significantly lower than those in healthy subjects, and were positively correlated with cognition levels in patients with ischemic stroke. Furthermore, a decrease in serum high-density lipoprotein levels in stroke patients was significantly correlated with a decrease in phosphorylated α-synuclein levels. Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury, some of them exhibited decreased cognitive function and reduced phosphorylated α-synuclein levels. Taken together, our results suggest that serum phosphorylated α-synuclein is a potential biomarker for poststroke cognitive impairment.
PubMed: 38845216
DOI: 10.4103/NRR.NRR-D-23-01348 -
Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases.Neuron May 2024Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in...
Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.
PubMed: 38843838
DOI: 10.1016/j.neuron.2024.05.006 -
Parkinsonism & Related Disorders Jun 2024Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with...
INTRODUCTION
Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD).
METHODS
We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure.
RESULTS
Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine.
CONCLUSIONS
These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.
PubMed: 38843617
DOI: 10.1016/j.parkreldis.2024.107024 -
Neurotoxicity Research Jun 2024Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease...
Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease (AD). Although it is assumed that alpha-synuclein ( -Syn), amyloid beta (A ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 M) for 24 h. ROT provokes loss of , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser) concomitantly with phosphorylation of -synuclein ( -Syn, Ser), induces accumulation of intracellular A (iA ), oxidized DJ-1 (Cys), as well as phosphorylation of TAU (Ser/Thr), increases the phosphorylation of c-JUN (Ser/Ser), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- -Syn, iA , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.
Topics: Rotenone; Cholinergic Neurons; Animals; Parkinson Disease; alpha-Synuclein; Dementia; Phenotype; Reactive Oxygen Species; Humans; Cells, Cultured
PubMed: 38842585
DOI: 10.1007/s12640-024-00705-3 -
EMBO Molecular Medicine Jun 2024Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We...
Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.
PubMed: 38839930
DOI: 10.1038/s44321-024-00083-5