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"Ma, Ming-Ming"
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Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease
Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (PD). However, there is no direct evidence in humans to support this role
1
–
5
. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.
Reduced meningeal lymphatic flow detected in patients with idiopathic Parkinson’s disease compared to patients with atypical Parkinsonian disorders and cognitively normal controls.
Journal Article
Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy
α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83
+/−
mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy.
Autonomic dysfunction is a feature of some α-synucleinopathies, but there are no models of pure autonomic dysfunction associated with α-synuclein. Here the authors describe a mouse model of pure autonomic dysfunction without motor dysfunciton by injection of pre-formed fibrils of α-synuclein to the stellate and celiac ganglia.
Journal Article
Dendritic Spines in Depression: What We Learned from Animal Models
Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms.
Journal Article
Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons
Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.
Long noncoding RNAs (lncRNAs) are known to regulate the DNA damage response (DDR), however their role in the brain is less well studied. Here, the authors demonstrate a neuron-specific role for Brain Specific DNA-damage Related lncRNA1 (BS-DRL1) and show BS-DRL1 modulates DDR by interacting with HMGB1 in a cell-type specific manner.
Journal Article
Identification of cuproptosis-related genes in Alzheimer’s disease based on bioinformatic analysis
Objective
To explore the role of cuproptosis in Alzheimer’s disease (AD).
Methods
An AD-related microarray dataset was downloaded from the Gene Expression Omnibus (GEO) database (GSE140830). Weighted gene co-expression network analysis was used to identify AD-related modular genes. The Venn analysis was performed to obtain module genes associated with apoptosis and cuproptosis. Besides, we conducted an enrichment analysis of overlapped genes and constructed the protein–protein interaction (PPI) network, followed by screening hub genes and those significantly associated with AD were used to construct models of apoptosis and cuproptosis, respectively. Further, receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA), and subgroup analysis were used to compare the AD prediction performance of two models. Finally, the accuracy and reliability of AD prediction models were verified by GSE26927.
Results
We obtained 42 module genes related to apoptosis and 9 module genes related to cuproptosis. The enrichment analysis results revealed MAPK signaling pathway as the common signaling pathway of apoptosis- and cuproptosis-related genes. Next, the hub genes associated with apoptosis (TRADD, FADD, BIRC2, and CASP2) and cuproptosis (MAP2K1, SLC31A1, and PDHB) in AD were identified, which were used to construct apoptosis and cuproptosis models to distinguish AD patients from the control group (
P
< 0.05). The ROC, DCA, and subgroup analysis results showed that apoptosis-related models and cuproptosis-related models had comparable ability in predicting AD. GSE26927 further confirmed that the two models have comparable predictive effects for AD.
Conclusions
The cuproptosis model had a certain performance in predicting AD. Three hub genes (MAP2K1, SLC31A1, and PDHB) closely related to cuproptosis in AD might serve as biomarkers for AD diagnosis and treatment.
Journal Article