Biology subjects

Park, J.-M.

Publications and source records attributed to Park, J.-M..

4 recordsLinked to original sources

bioRxiv2024

Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies

GBA is the major risk gene for Parkinsons disease (PD) and Dementia with Lewy Bodies (DLB), two common -synucleinopathies with cognitive deficits. We investigated the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but lacked PD-like motor deficits or -synuclein pathology. Conversely, SNCA tg mice displayed age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibited both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho--synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validated these findings. Our results indicate that Gba mutations, while exacerbating pre-existing -synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through -synuclein-independent mechanisms, involving dysfunction in SV endocytosis.

neuroscience↗

bioRxiv2022

Single-cell transcriptomic and proteomic analysis of Parkinson's disease Brains

Parkinsons disease (PD) is a prevalent neurodegenerative disorder where recent evidence suggests pathogenesis may be mediated by inflammatory processes. The molecular architecture of the disease remains to be fully elucidated. We performed single-nucleus transcriptomics and unbiased proteomics using postmortem tissue obtained from the prefrontal cortex of 12 individuals with late-stage PD and age-matched controls. We analyzed [~]80,000 nuclei and identified eight major cell types, including brain-resident T cells, each with distinct transcriptional changes in line with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem tissue, we found that -synuclein pathology is inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in prefrontal cortex that were preferentially downregulated in PD. Strikingly, comparing this dataset to a regionally similar published analysis for Alzheimers disease (AD), we found no common differentially expressed genes in neurons, but identified many shared differentially expressed genes in glial cells, suggesting that disease etiology in PD and AD are likely distinct. These data are presented as a resource for interrogating the molecular and cellular basis of PD and other neurodegenerative diseases. One Sentence SummaryWe provide an extensive single cell analysis profiling nearly 80,000 brain nuclei from prefrontal cortex of late-stage Parkinsons disease brains, demonstrate that -synuclein pathology is inversely correlated with chaperone expression in excitatory neurons, found a selective abatement of neuron-astrocyte interactions with enhanced neuroinflammation, and augmented the study with proteomic analysis and cross-comparisons with Alzheimers disease datasets, providing valuable insights into the pathways of neurodegeneration and a deep definition of the underlying molecular pathology for Parkinsons disease.

neuroscience↗

bioRxiv2020

Antiviral effects of miRNAs in extracellular vesicles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mutations in SARS-CoV-2 RNA virus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 2019 (COVID-19). No treatment is available. Micro-RNAs (miRNAs) in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are potential novel therapeutic agents because of their ability to regulate gene expression by inhibiting mRNA. Thus, they may degrade the RNA genome of SARS-CoV-2. EVs can transfer miRNAs to recipient cells and regulate conditions within them. MSC-EVs harbor major therapeutic miRNAs that play important roles in the biological functions of virus-infected host cells. Here, we examined their potential impact on viral and immune responses. MSC-EVs contained 18 miRNAs predicted to interact directly with the 3 UTR of SARS-CoV-2. These EVs suppressed SARS-CoV-2 replication in Vero E6 cells. In addition, five major miRNAs suppressed virus activity in a luciferase reporter assay by binding the 3 UTR. MSC-EVs showed strong regenerative effects and potent anti-inflammatory activity which may prevent lethal cytokine storms. We confirmed that EVs regulated inflammatory responses by several cell types, including human brain cells that express the viral receptor ACE2, suggesting that the brain may be targeted by SARS-CoV-2. miRNAs in MSC-EVs have several advantages as therapeutic agents against SARS-CoV-2: 1) they bind specifically to the viral 3 UTR, and are thus unlikely to have side effects; 2) because the 3 UTR is highly conserved and rarely mutates, MSC-EV miRNAs could be used against novel variants arising during viral replication; and 3) unique cargoes carried by MSC-EVs can have diverse effects, such as regenerating damaged tissue and regulating immunity.

molecular biology↗

bioRxiv2019

Trueness of digital intraoral impression in reproducing multiple implant position

The aim of this study was to evaluate the trueness of 5 intraoral scanners (IOSs) for digital impression of simulated implant scan bodies in a complete-arch model. A 3D printed full-arch mandible model made of Co-Cr with a total of 6 bilaterally positioned cylinders in the canine, second premolar, and second molar area served as the study model. Digital scans of the model were made with a reference scanner (steroSCAN neo) and 5 IOSs (CEREC Omnicam, CS3600, i500, iTero Element, and TRIOS 3) (n=10). For each IOSs dataset, the XYZ coordinates of the cylinders were obtained from the reference point and the deviations from the reference scanner were calculated using a 3D reverse engineering program (Rapidform). The trueness values were analyzed by Kruskal-Wallis test and Mann-Whitney post hoc test. Direction and amount of deviation differed among cylinder position and among IOSs. Regardless of the IOS type, the cylinders positioned on the left second molar, nearest to the scanning start point, showed the smallest deviation. The deviation generally increased further away from scanning start point towards the right second molar. TRIOS 3 and i500 outperformed the other IOSs for complete-arch digital impression. The accuracy of the CEREC Omnicam, CS3600, and iTero Element were similar on the left side, but they showed more deviations on the right side of the arch when compared to the other IOSs. The accuracy of IOS is still an area that needs to be improved.

scientific communication and education↗