DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency

Nam Younwoo,Na Jiyeon,Ma Shi-Xun,Park Ha-Eun,Park Hyeonwoo,Lee Eunmin,Kim Hyerynn,Jang Sang-Min,Ko Han Seok,Kim Sangjune 한국유전학회 2024 Genes & Genomics Vol.46 No.5

Background GBA1 mutations are the most common genetic risk factor for development of Parkinson’s disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown. Objective In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction. Methods GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice. Results We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction. Conclusion Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations. Background GBA1 mutations are the most common genetic risk factor for development of Parkinson’s disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown. Objective In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction. Methods GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice. Results We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction. Conclusion Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.

내부로 공급되는 공기 유량에 따른 에틸렌 확산화염의 매연 방출 현상

남연우(Younwoo Nam),문두성(Dusung Moon),이원남(Wonnam Lee) 한국연소학회 2010 KOSCOSYMPOSIUM논문집 Vol.- No.41

The characteristics of soot formation with air addition have been studied experimentally using a concentric co-flow diffusion burner, which provides the stratified air mixture through an inner nozzle. Integrated soot volume fraction, temperature and scattering images of diffusion flames were measured using a laser light extinction method, two-color pyrometry and 2-D laser light scattering technique, respectively. An ethylene diffusion flame started to emit soot with a small amount of air flow through an inner nozzle, which could be explained with the enhanced soot formation process due to the oxygenated species assisted pyrolysis. The increase of air flow rate up to 250 sccm transformed a soot emitting flame into a non-emitting flame without inner flame. Further increase of air flow rate created an inner flame and changed the flame into a soot emitting flame. When air flow rate was decreased again, the flame was changed back to a emitting flame; however, the presence of an inner flame altered the soot formation and oxidation characteristics of the flame and enhanced the soot formation process. The oxygenated species assisted pyrolysis, the radiation heat loss and the temperature effect of inner flames would determine the characteristics of soot production/oxidation of an ethylene diffusion flame with air flow inside.

함산소 연료 및 산화제 첨가에 따른 에틸렌화염의 매연 생성 특성 변화

남연우(Younwoo Nam),이원남(Wonnam Lee) 한국연소학회 2008 KOSCOSYMPOSIUM논문집 Vol.- No.-

The soot formation characteristics of ethylene diffusion flames have been experimentally investigated in order to understand the synergistic effect of oxygenated fuel. The role of methyl radical and/or oxygenated species assisted pyrolysis on the soot formation process could explain the increase of soot volume fraction with DME or ethanol mixed to ethylene. The addition of N₂O to ethylene fuel only enhances the soot formation process that is similar to the pure oxygen addition case. However, the addition of oxygenated species might reduce the soot amount in oxidation region, and therefore, it might suppress the overall soot formation process in turbulent flames.

EGR cooler Fouling이 냉각 성능에 미치는 영향에 관한 연구

남연우(Younwoo Nam),오광철(Kwangchul Oh),김덕진(Dukjin Kim),김종훈(Jonghun Kim),이천환(Chunhwan Lee),이춘범(Chunbeom Lee) 한국자동차공학회 2009 한국자동차공학회 부문종합 학술대회 Vol.2009 No.4

Understanding the exhaust gas recirculation (EGR) cooler fouling in diesel engine is important factor in the durability characteristic of the EGR system. We develope the test rig and PM feeder using carbon black to examine the effect of fouling on EGR cooler devices those were consisted of flat and spiral type tube. The EGR cooler fouling process is a complex interaction involving heat exchanger shape, boundary condition, constitutes, chemistry and operating mode. As the soot deposited to EGR cooler, these formed a thin deposit layer that was less heat exchange than the fresh status of tube enclosing the exhaust gas, resulting in lower heat exchange effectiveness in both type coolers. But these deposits caused different results in pressure drop, it is increased in flat type, but decreased in spiral type of EGR cooler. A cause was estimated from a change of the flow structure and a decrease of contac area as the EGR cooler fouling.

층류확산화염의 불안정성에 대한 매연생성 특성의 역할

남연우(Younwoo Nam),이원남(Wonnam Lee) 한국연소학회 2010 한국연소학회지 Vol.15 No.3

In this study, soot formation characteristics on the instability of laminar diffusion flames were investigated experimentally using a concentric co-flow burner. When a small amount of air was supplied through an inner nozzle, a stable propane laminar diffusion flame became unstable and began to oscillate mainly due to the dilution effect. The increase of air flow rate transformed an oscillating non-sooting flame into a stable nonsooting flame. When the air flow rate was continuously increased an inner flame was formed and the flame was changed to an oscillating sooting flame, an oscillating non-sooting flame and finally a stable non-sooting hollow flame. When the air flow rate was decreased, a non-sooting hollow flame was eventually changed back to a stable non-sooting flame. The presence of an inner flame, however, altered the soot formation characteristics of a flame. More soot production was observed with the presence of an inner flame. The increased or decreased soot formation/oxidation rates, the radiation heat loss, and the heating effect of inner flames are most likely to be responsible for the observed instability of laminar diffusion flames.

화염의 유동장과 온도에 따른 동축류 확산화염의 불안정 특성

남연우(Younwoo Nam),배승만(Seungman Bae),이원남(Wonnam Lee) 한국연소학회 2010 KOSCOSYMPOSIUM논문집 Vol.- No.40

Flow and temperature characteristics were investigated when co-flow diffusion flames become unstable. Soot concentration, temperature and velocity profiles of diffusion flames were measured using a laser light extinction method and modulated LII signals near the smoke-points or unstable conditions. For methane and ethane diffusion flames, soot concentration is low and flame temperature remains high, and therefore, the flame becomes unstable when the fuel flow rate increases. For ethylene and propylene diffusion flames, however, soot concentration is high and flame temperature becomes low, and the flame starts to emit soot before it becomes unstable with the increase of fuel flow rate. For propane and n-butane diffusion flames, the flame becomes unstable and emits soot at the same time when the fuel flow rate is increased. When soot concentration becomes high, the increased radiation heat loss lowers the flame temperature, and therefore, the flame tends to emit soot before it reaches to the unstable condition. On the other hand, when the soot concentration in a flame is low, the flame temperature remains high since the radiation heat loss is less. As a result, the flame can be long enough to become unstable or the flow velocity can be accelerated fast enough to develop the instability.

프로판 확산화염의 불안정성에 대한 내부화염의 역할

남연우(Younwoo Nam),문두성(Dusung Moon),이원남(Wonnam Lee) 한국연소학회 2009 KOSCOSYMPOSIUM논문집 Vol.- No.39

The instability of laminar propane diffusion flames due to the existence of an inner inverse diffusion flame has been investigated using a concentric co-flow burner. A stable laminar propane diffusion flame started to oscillate with a small amount of air flow through an inner nozzle. Further increase of air flow rate changed the flame into a stable non-sooting, an oscillating and sooting, an oscillating non-sooting, and a stable non-sooting flame in sequence. Starting from high air flow rate, the decrease of air flow rate changed the flame back to a stable non-sooting flame via an oscillating non-sooting, an oscillating sooting and an oscillating non-sooting flame. The increased or decreased soot formation and oxidation rates, radiation heat loss, and heating by an inner flame are most likely to be responsible for the characteristics of a propane diffusion flames on instability and soot production.

EGR Cooler 내부 형상에 따른 Fouling이 냉각 성능에 미치는 영향

남연우(Younwoo Nam),오광철(KwangChul Oh),이천환(Chunhwan Lee),이춘범(Chunbeom Lee),이원남(Wonnam Lee) 한국자동차공학회 2011 한국 자동차공학회논문집 Vol.19 No.1

매연입자 발생장치를 이용한 디젤 배기가스 내 매연 및 유기성 용해물질(SOF) 모사

남연우(Younwoo Nam),오광철(Kwangchul Oh),이천환(Chunhwan Lee),이춘범(Chunbeom Lee) 한국자동차공학회 2008 한국자동차공학회 춘 추계 학술대회 논문집 Vol.- No.-

화염 발광 가시화를 이용한 성층화된 동축류 화염 특성 분석

안태국(Taekook Ahn),남연우(Younwoo Nam),이원남(Wonnam Lee) 한국연소학회 2012 KOSCOSYMPOSIUM논문집 Vol.- No.44