Biology subjects

Kim, H.-B.

Publications and source records attributed to Kim, H.-B..

4 recordsLinked to original sources

bioRxiv2024

Pathologic α-Synuclein-NOD2 Interaction and RIPK2 Activation Drives Microglia-Induced Neuroinflammation in Parkinson's Disease

Pathological aggregation of -Synuclein (-Syn) and neuroinflammation are closely linked to Parkinsons disease (PD). However, the specific regulators of the neuroinflammation caused by pathological -syn remain obscure. In this study, we show that NOD2/RIPK2 signaling is a crucial regulator of neuroinflammation in PD. Pathological -syn binds to NOD2, causing self-oligomerization and complex formation with RIPK2, leading to RIPK2 ubiquitination and activation of MAPK and NF-kB. Notably, this NOD2/RIPK2 signaling is particularly active in microglia of human PD brains and the -Syn preformed fibril (-Syn PFF) mouse model. Depleting NOD2 or RIPK2 reduces neuroinflammation and protects against dopamine neuron degeneration in a pathologic -Syn mouse model by blocking the formation of neurotoxic reactive astrocytes caused by microglia activation. The discovery of NOD2/RIPK2 signaling as a key regulator of neuroinflammation in PD provides a new understanding of -Syn-driven neuroinflammation and neurodegeneration in PD and a potential new therapeutic strategy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/580982v2_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@10c010aorg.highwire.dtl.DTLVardef@1183b23org.highwire.dtl.DTLVardef@1d289dborg.highwire.dtl.DTLVardef@158b6ef_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefPathological -Synuclein (-Syn) binds to the microglial NOD2 protein, which in turn triggers NOD2/RIPK2 complex and RIPK2 phosphorylation/ubiquitination. This process activates the NF-kB/MAPK pathways, ultimately leading to neurotoxic reactive astrocyte-induced dopaminergic neurodegeneration. Depletion of RIPK2 (RIPK2 KO) or NOD2 (NOD2) protects dopamine neurons in a mouse model of Parkinsons disease (PD). These findings provide insights into -Syn-driven neuroinflammation and offer potential therapeutic strategies for PD. HighlightsNOD2/RIPK2 signaling is identified as a crucial regulator of neuroinflammation in PD. NOD2/RIPK2 signaling is highly active in microglia in human PD brains and -Syn PFF mouse models. Pathological -Syn binds to NOD2, triggering self-oligomerization and RIPK2 complex formation, leading to MAPK and NF-kB activation Genetic depletion of NOD2 or RIPK2 reduces neuroinflammation and protects dopamine neurons by blocking the formation of neurotoxic reactive astrocytes.

neuroscience↗

bioRxiv2023

Antibody-based immunotherapy targeting FAM19A5 reverses synaptic loss and improves cognitive function in Alzheimer's disease.

IntroductionAlzheimers disease (AD) is characterized by the dysregulation of synaptic balance, with progressive loss of synapses outpacing formation, ultimately leading to cognitive decline. However, the lack of effective strategies for restoring lost synapses poses a major barrier to improving clinical outcomes. MethodsWe developed NS101, a monoclonal antibody targeting FAM19A5, a brain-secreted protein. Its preclinical efficacy in restoring synapses and cognition was evaluated using APP/PS1 and P301S mice. The clinical safety and target engagement of NS101 were examined in human participants. ResultsFAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to synapse reduction. Blocking this interaction with NS101 normalized the rate of synapse elimination in AD mice. This synaptic rebalancing restored the number and function of synapses, resulting in improved cognition. Systemically administered NS101 facilitated the transport of brain FAM19A5 into the bloodstream. DiscussionTargeting FAM19A5 may hold clinical promise for treating AD by restoring synaptic balance.

neuroscience↗

bioRxiv2023

Methylglyoxal is the main culprit to impairing neuronal function: mediated through tryptophan depletion.

Depression is a common and prevalent illness and the exact cause of major depressive disorder is not known. Here, we investigated how methylglyoxal (MGO) stress induces depression and unveiled the potential molecular mechanism. Our in vivo results suggested that MGO caused depression in mice, confirmed by several behavioral tests. Interestingly, it halted the mices brains tryptophan levels and its related neurotransmitters. In addition, MGO induced a reduction in the number of cells in different hippocampal regions. Moreover, it decreased tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 1 (TPH2) levels in the brain and large intestine. Surprisingly, MGO showed the highest affinity and trapping ability toward tryptophan. Most importantly, combined treatment with MGO-tryptophan displayed similar effects as those exhibited by the tryptophan-null treatment in neuronal cells, which included neuronal apoptosis, decrease TPH1 and TPH2 levels, and inhibition of neuronal outgrowth. However, tryptophan treatment improved MGO induced depression-like behavior of mice and recovered the loss of neuronal and hippocampal cells. Subsequently, it also induced MGO detoxifying factors, tryptophan levels, and reduces inflammation in the intestine. Collectively, our data revealed that MGO induced depression facilitated by neuronal and synaptic dysfunction is mediated through the disturbance of tryptophan metabolism in the brain and intestine.

neuroscience↗

bioRxiv2017

Label-free non-invasive quantitative measurement of lipid contents in individual microalgal cells using refractive index tomography

Microalgae are promising candidates for biofuel production due to their high lipid content. To facilitate utilization of the microalgae for biofuel, rapid quantification of the lipid contents in microalgae is necessary. However, conventional methods based on the chemical extraction of lipids require a time-consuming destructive extraction process. Here, we demonstrate label-free, non-invasive, rapid quantification of the lipid contents in individual micro-algal cells measuring the three-dimensional refractive index tomograms. We measure three-dimensional refractive index distributions within Nannochloropsis oculata cells and find that lipid droplets are identifiable in tomograms by their high refractive index. In addition, we alter N. oculata under nitrogen deficiency by measuring the volume, lipid weight, and dry cell weight of individual cells. Characterization of individual cells allows correlative analysis between the lipid content and size of individual cells.

bioengineering↗