Park S et al. (2017) F1000Res "RNAi targeting Caenorhabditis elegans -arrestins marginally affects lifespan."

An SWA, Lee SV, Park HH, Lee D, Lee Y, Artan M, Son HG, Jeong DE, Jung Y, Park S, Hwang W

[F1000Res, 2017]

Background: -arrestins are a family of proteins that are implicated in multiple biological processes, including metabolism and receptor desensitization. Methods: Here, we sought to examine the roles of -arrestins in the longevity of Caenorhabditis elegans through an RNA interference screen. Results: We found that knocking down each of 24 out of total 29 C. elegans -arrestins had small or no effects on lifespan. Thus, individual C. elegans -arrestins may have minor effects on longevity. Conclusions: This study will provide useful information for future research on the functional role of -arrestins in aging and longevity.

Park S et al. (2008) PLoS One "Enhanced Caenorhabditis elegans locomotion in a structured microfluidic environment."

Hwang H, Ryu WS, Park S, Martinez F, Austin RH, Nam SW

[PLoS One, 2008]

BACKGROUND: Behavioral studies of Caenorhabditis elegans traditionally are done on the smooth surface of agar plates, but the natural habitat of C. elegans and other nematodes is the soil, a complex and structured environment. In order to investigate how worms move in such environments, we have developed a technique to study C. elegans locomotion in microstructures fabricated from agar. METHODOLOGY/PRINCIPAL FINDINGS: When placed in open, liquid-filled, microfluidic chambers containing a square array of posts, we discovered that worms are capable of a novel mode of locomotion, which combines the fast gait of swimming with the more efficient movements of crawling. When the wavelength of the worms matched the periodicity of the post array, the microstructure directed the swimming and increased the speed of C. elegans ten-fold. We found that mutants defective in mechanosensation (mec-4, mec-10) or mutants with abnormal waveforms (unc-29) did not perform this enhanced locomotion and moved much more slowly than wild-type worms in the microstructure. CONCLUSION/SIGNIFICANCE: These results show that the microstructure can be used as a behavioral screen for mechanosensory and uncoordinated mutants. It is likely that worms use mechanosensation in the movement and navigation through heterogeneous environments.

Park S et al. (2020) Sci Adv "VRK-1 extends life span by activation of AMPK via phosphorylation."

Kim KT, Lee SV, Jung Y, Park S, Artan M, Park HH, Shin WS, Hwang AB, Han SH

[Sci Adv, 2020]

Vaccinia virus-related kinase (VRK) is an evolutionarily conserved nuclear protein kinase. VRK-1, the single <i>Caenorhabditis elegans</i> VRK ortholog, functions in cell division and germline proliferation. However, the role of VRK-1 in postmitotic cells and adult life span remains unknown. Here, we show that VRK-1 increases organismal longevity by activating the cellular energy sensor, AMP-activated protein kinase (AMPK), via direct phosphorylation. We found that overexpression of <i>vrk-1</i> in the soma of adult <i>C. elegans</i> increased life span and, conversely, inhibition of <i>vrk-1</i> decreased life span. In addition, <i>vrk-1</i> was required for longevity conferred by mutations that inhibit <i>C. elegans</i> mitochondrial respiration, which requires AMPK. VRK-1 directly phosphorylated and up-regulated AMPK in both <i>C. elegans</i> and cultured human cells. Thus, our data show that the somatic nuclear kinase, VRK-1, promotes longevity through AMPK activation, and this function appears to be conserved between <i>C. elegans</i> and humans.

Park S et al. (2024) Curr Biol "Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology."

Noblett N, Wehman AM, Pitts L, Colavita A, Chisholm AD, Park S, Jin Y

[Curr Biol, 2024]

Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain the morphology of mature neurons. Loss of function in C.&#xa0;elegans dip-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find that dip-2 mutants display specific genetic interactions with sax-2, the C.&#xa0;elegans ortholog of Drosophila Furry and mammalian FRY. Combined loss of dip-2 and sax-2 results in failure to maintain neuronal morphology and elevated release of neuronal extracellular vesicles (EVs). By screening for suppressors of dip-2(0) sax-2(0) double mutant defects, we identified gain-of-function (gf) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A that restore normal neuronal morphology and normal levels of EV release to dip-2(0) sax-2(0) double mutants. Neuron-specific knockdown suggests that PAD-1(gf) can act cell autonomously in neurons. PAD-1(gf) displays increased association with the plasma membrane in oocytes and inhibits EV release in multiple cell types. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains neuronal morphology and modulates EV release.

Park S et al. (2016) Mol Cells "DNA Strand Breaks in Mitotic Germ Cells of Caenorhabditis elegans Evaluated by Comet Assay."

Park S, Ahn B, Choi S

[Mol Cells, 2016]

DNA damage responses are important for the maintenance of genome stability and the survival of organisms. Such responses are activated in the presence of DNA damage and lead to cell cycle arrest, apoptosis, and DNA repair. In Caenorhabditis elegans, double-strand breaks induced by DNA damaging agents have been detected indirectly by antibodies against DSB recognizing proteins. In this study we used a comet assay to detect DNA strand breaks and to measure the elimination of DNA strand breaks in mitotic germline nuclei of C. elegans. We found that C. elegans brc-1 mutants were more sensitive to ionizing radiation and camptothecin than the N2 wild-type strain and repaired DNA strand breaks less efficiently than N2. This study is the first demonstration of direct measurement of DNA strand breaks in mitotic germline nuclei of C. elegans. This newly developed assay can be applied to detect DNA strand breaks in different C. elegans mutants that are sensitive to DNA damaging agents.

Park S et al. (2017) Sci Rep "Genetic deficiency in neuronal peroxisomal fatty acid -oxidation causes the interruption of dauer development in Caenorhabditis elegans."

Paik YK, Park S

[Sci Rep, 2017]

Although peroxisomal fatty acid (FA) -oxidation is known to be critical for animal development, the cellular mechanisms that control the manner in which its neuronal deficiency causes developmental defects remain unclear. To elucidate the potential cellular consequences of neuronal FA metabolic disorder for dauer development, an alternative developmental process in Caenorhabditis elegans that occurs during stress, we investigated the sequential effects of its corresponding genetic deficiency. Here, we show that the daf-22 gene in peroxisomal FA -oxidation plays a distinct role in ASK neurons, and its deficiency interrupts dauer development even in the presence of the exogenous ascaroside pheromones that induce such development. Un-metabolized FAs accumulated in ASK neurons of daf-22 mutants stimulate the endoplasmic reticulum (ER) stress response, which may enhance the XBP-1 activity that promotes the transcription of neuronal insulin-like peptides. These sequential cell-autonomous reactions in ASK neurons then activate insulin/IGF-1 signaling, which culminates in the suppression of DAF-16/FOXO activity. This suppression results in the interruption of dauer development, independently of pheromone presence. These findings suggest that neuronal peroxisomal FA -oxidation is indispensable for animal development by regulating the ER stress response and neuroendocrine signaling.

Park S et al. (2022) Antioxidants (Basel) "Anti-Oxidant and Anti-Aging Effects of Phlorizin Are Mediated by DAF-16-Induced Stress Response and Autophagy in Caenorhabditis elegans."

Park S, Park SK

[Antioxidants (Basel), 2022]

Phlorizin (phloridzin) is a polyphenolic phytochemical primarily found in unripe Malus (apple). It is a glucoside of phloretin and acts as an inhibitor of renal glucose transport, thus lowering blood glucose. The objective of this study was to determine effects of dietary supplementation with phlorizin on stress response, aging, and age-related diseases using Caenorhabditis elegans as a model system. Survival after oxidative stress or ultraviolet irradiation was significantly increased by pre-treatment of phlorizin. Dietary supplementation with phlorizin also significantly extended lifespans without reducing fertility. Age-related decline of muscle function was delayed by supplementation with phlorizin. Phlorizin induced the expression of stress-responsive genes hsp-16.2 and sod-3 and nuclear localization of DAF-16, a FOXO transcription factor modulating stress response and lifespan in C. elegans. Amyloid-beta-induced toxicity was significantly reduced by phlorizin. This effect was dependent on DAF-16 and SKN-1. Increased mortality induced with a high-glucose diet was partially prevented by phlorizin via SKN-1. Inactivation of dopaminergic neurons observed in a Parkinson's disease model was completely recovered by supplementation with phlorizin. Genetic analysis suggests that lifespan extension by phlorizin is mediated through oxidative stress response and autophagy. Taken together, these data suggest that phlorizin has strong anti-oxidant and anti-aging activities with potential to be developed as a novel anti-oxidant nutraceutical against aging and age-related diseases.

Park S et al. (2020) Aging Cell "Diacetyl odor shortens longevity conferred by food deprivation in C.elegans via downregulation of DAF-16/FOXO."

Lee SV, Park HH, Jung Y, Lee JI, Park S, Jeong DE, Kim SS, Artan M, Choi Y, Kim K, Son HG

[Aging Cell, 2020]

Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors.

Park S et al. (2017) J Neurosci "UNC-18 and Tomosyn antagonistically control synaptic vesicle priming downstream of UNC-13 in C. elegans."

Ma K, Kalia L, Bin NR, Gao S, Sitarska E, Tien CW, Xu J, Wong R, Sugita S, Turlova E, Monnier PP, Sun HS, Yu B, Park S, Algouneh A, Zhen M, Wang S, Shahid W, Siriya P, Sugita K, Rizo J, Feng ZP

[J Neurosci, 2017]

Munc18-1/UNC-18 is believed to prime SNARE-mediated membrane fusion, yet the underlying mechanisms remain enigmatic. Here, we examined how potential gain-of-function mutations of Munc18-1/UNC-18 affect locomotory behavior and synaptic transmission, and how Munc18-1-mediated priming is related to Munc13-1/UNC-13 and Tomosyn/TOM-1, positive and negative SNARE regulators, respectively. We show that a Munc18-1(P335A)/UNC-18(P334A) mutation leads to significantly increased locomotory activity and acetylcholine release in C. elegans, as well as enhanced synaptic neurotransmission in cultured mammalian neurons. Importantly, similar to tom-1 null mutants, unc-18(P334A) mutants partially bypass the requirement of UNC-13. Moreover, unc-18(P334A) and tom-1 null mutations confer a strong synergy in suppressing the phenotypes of unc-13 mutants. Through biochemical experiments, we demonstrate that Munc18-1(P335A) exhibits enhanced activity in SNARE complex formation as well as in binding to the preformed SNARE complex, and partially bypasses the Munc13-1 requirement in liposome fusion assays. Our results indicate that Munc18-1/UNC-18 primes vesicle fusion downstream of Munc13-1/UNC-13 by templating SNARE complex assembly, and acts antagonistically with Tomosyn/TOM-1.SIGNIFICANCE STATEMENTAt presynaptic sites, SNARE-mediated membrane fusion is tightly regulated by several key proteins including Munc18/UNC-18, Munc13/UNC-13 and Tomosyn/TOM-1. However, how these proteins interact with each other to achieve the precise regulation of neurotransmitter release remains largely unclear. Using C. elegans as an in vivo model, we found that a gain-of-function mutant of UNC-18 increases locomotory activity and synaptic acetylcholine release, that it partially bypasses the requirement of UNC-13 for release, and that this bypass is synergistically augmented by the lack of TOM-1. We also elucidated the biochemical basis for the gain-of-function caused by this mutation. Thus, our study provides novel mechanistic insights into how Munc18/UNC-18 primes synaptic vesicle release and how this protein interacts functionally with Munc13/UNC-13 and Tomosyn/TOM-1.

Park S et al. (2020) Int J Mol Sci "A Molecular Basis for Reciprocal Regulation between Pheromones and Hormones in Response to Dietary Cues in C. elegans."

Park S, Park JY, Paik YK

[Int J Mol Sci, 2020]

Under stressful conditions, the early larvae of C. elegans enter dauer diapause, a non-aging period, driven by the seemingly opposite influence of ascaroside pheromones (ASCRs) and steroid hormone dafachronic acids (DAs). However, the molecular basis of how these small molecules engage in competitive crosstalk in coordination with insulin/IGF-1 signaling (IIS) remains elusive. Here we report a novel transcriptional regulatory pathway that seems to operate between the ASCR and DA biosynthesis under ad libitum (AL) feeding conditions or bacterial deprivation (BD). Although expression of the ASCR and DA biosynthetic genes reciprocally inhibit each other, ironically and interestingly, such dietary cue-mediated modulation requires the presence of the competitors. Under BD, induction of ASCR biosynthetic gene expression required DA, while ASCR suppresses the expression of the DA biosynthetic gene daf-36. The negative regulation of DA by ASCR was IIS-dependent, whereas daf-36 regulation appeared to be independent of IIS. These observations suggest that the presence of ASCR determines the IIS-dependency of DA gene expression regardless of dietary conditions. Thus, our work defines a molecular basis for a novel reciprocal gene regulation of pheromones and hormones to cope with stressful conditions during development and aging.