Phosphorylation of p62 by AMP-activated protein kinase mediates autophagic cell death in adult hippocampal neural stem cells

Ha, Shinwon,Jeong, Seol-Hwa,Yi, Kyungrim,Chung, Kyung Min,Hong, Caroline Jeeyeon,Kim, Seong Who,Kim, Eun-Kyoung,Yu, Seong-Woon American Society for Biochemistry and Molecular Bi 2017 The Journal of biological chemistry Vol.292 No.33

<P>In the adult brain, programmed death of neural stem cells is considered to be critical for tissue homeostasis and cognitive function and is dysregulated in neurodegeneration. Previously, we have reported that adult rat hippocampal neural (HCN) stem cells undergo autophagic cell death (ACD) following insulin withdrawal. Because the apoptotic capability of the HCN cells was intact, our findings suggested activation of unique molecular mechanisms linking insulin withdrawal to ACD rather than apoptosis. Here, we report that phosphorylation of autophagy-associated protein p62 by AMP-activated protein kinase (AMPK) drives ACD and mitophagy in HCN cells. Pharmacological inhibition of AMPK or genetic ablation of the AMPK alpha 2 subunit by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing suppressed ACD, whereas AMPK activation promoted ACD in insulin-deprived HCN cells. We found that following insulin withdrawal AMPK phosphorylated p62 at a novel site, Ser-293/Ser-294 (in rat and human p62, respectively). Phosphorylated p62 translocated to mitochondria and induced mitophagy and ACD. Interestingly, p62 phosphorylation at Ser-293 was not required for staurosporine-induced apoptosis in HCN cells. To the best of our knowledge, this is the first report on the direct phosphorylation of p62 by AMPK. Our data suggest that AMPK-mediated p62 phosphorylation is an ACD-specific signaling event and provide novel mechanistic insight into the molecular mechanisms in ACD.</P>

Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.

Chung, Kyung Min,Park, Hyunhee,Jung, Seonghee,Ha, Shinwon,Yoo, Seung-Jun,Woo, Hanwoong,Lee, Hyang Ju,Kim, Seong Who,Kim, Eun-Kyoung,Moon, Cheil,Yu, Seong-Woon AlphaMed Press 2015 Stem Cells Vol.33 No.10

<P>Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death. Stem Cells 2015;33:3052-3064.</P>

소방공무원과 외상 후 스트레스 장애

류지아,하은희,정최경희,김지은,박신원,김현주,Ryu, Jia,Ha, Eunhee,Jeong-Choi, Kyunghee,Kim, Jieun E.,Park, Shinwon,Kim, Hyunjoo 대한생물정신의학회 2017 생물정신의학 Vol.24 No.1

Occupational hazards of firefighting and rescue works include frequent exposure to emergencies and life-threatening situations. These stressful work conditions of being constantly under pressure and exposed to potentially traumatic events put them at higher risk of developing posttraumatic stress disorder (PTSD), compared to the general population. PTSD is a potentially debilitating mental disorder, due to persistent intrusive thoughts, negative alterations of mood and cognition, hypervigilance, avoidance of similar situations and reminders, and re-experiences of the traumatic event. Previous studies have shown a relatively high prevalence of PTSD among firefighters, indicating the need for a systematic approach of early detection and prevention. Therefore, a critical review of the current literature on PTSD in firefighters would provide valuable insights into developing effective prevention and intervention programs. Literature indicated that there are risk factors of PTSD in firefighters, such as pre-existing depression, anxiety, sleep disorders, occupational stress, physical symptoms, and binge drinking, whereas social support and adequate rewards are protective factors. Although there are differences in the prevalence of PTSD across studies, partly due to various assessment tools utilized, different sample sizes, and sample characteristics, over one tenth of the firefighters were estimated to have PTSD. The current review warrants further investigations to precisely assess PTSD and co-morbid mental disorders, functional outcomes, and associated factors, and to develop evidence-based preventive and interventional programs to help firefighters with PTSD.

GSK3B induces autophagy by phosphorylating ULK1

Ryu Hye Young,Kim Leah Eunjung,Jeong Hyeonjeong,Yeo Bo Kyoung,Lee Ji-Won,Nam Hyeri,Ha Shinwon,An Hyun-Kyu,Park Hyunhee,Jung Seonghee,Chung Kyung Min,Kim Jiyea,Lee Byung-Hoon,Cheong Heesun,Kim Eun-Kyou 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis.

리뷰 : 화재현장에서 노출될 수 있는 화학적 유해물질과 파킨슨병 간의 관련성

예신희,김현주,정최경희,김지은,박신원,이유민,하은희,Ye, Shinhee,Kim, Hyunjoo,Jeong-Choi, Kyunghee,Kim, Jieun E.,Park, Shinwon,Lee, Yumin,Ha, Eun-Hee 대한생물정신의학회 2017 생물정신의학 Vol.24 No.1

Previous studies have found that firefighters have a tenfold higher prevalence of Parkinson's disease (PD) compare to the general population. Firefighters are constantly exposed to various occupational hazards including toxic chemicals of fire residue and the toxic chemicals can effects development and progression of PD. Nevertheless, there were no studies about the association between exposure to chemical byproducts of combustion and the development of PD among firefighters. Thus the aim of this study is to look into existing researches regarding the effect of chemical byproducts of combustion on the development of PD. An extensive literature search was conducted to identify harmful chemical components of smoke and fire residue, using the PubMed database during November of 2016. We searched for relevant articles by combining several keywords that contained "Parkinson's disease" and each of the different toxic chemicals, yielding a total of 1401 articles. After applying the selection criteria, 12 articles were chosen. Chemical substances reported to have a harmful effect on PD, in at least one article, were carbon monoxide, toluene, manganese and lead. Carbon monoxide and metal substances including manganese and lead were found to be associated with an increased PD risk in more than two articles. There was a heightened risk of PD in firefighters due to exposure of chemical byproducts of combustion including carbon monoxide, toluene, manganese and lead. However, to the best of our knowledge, to support this result we need more systematic epidemiological studies about these risk factors of PD among firefighters. In addition, further studies for the effects of prolonged exposure to toxic fire residue on the development and progression of PD in firefighters are needed.

Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation

Kim Dong-Kyu,Jeong Hyobin,Bae Jingi,Cha Moon-Yong,Kang Moonkyung,Shin Dongjin,Ha Shinwon,Hyeon Seung Jae,Kim Hokeun,Suh Kyujin,Choi Mi-Sun,Ryu Hoon,Yu Seong-Woon,Kim Jong-Il,Kim Yeon-Sook,Lee Sang-Won 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aβ) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer’s disease (AD) model mice, Aβ-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.

인지 및 행동영역에서 교대 근무의 유해적인 영향 : 비판적 고찰

이수지,박창현,하은지,박신원,홍혜진,박수현,마지영,강일향,강한,송병훈,김정윤,김지은,Lee, Suji L.,Park, Chang-hyun,Ha, Eunji,Park, Shinwon,Hong, Haejin,Park, Su Hyun,Ma, Jiyoung,Kang, Ilhyang,Kang, Hahn,Song, William Byunghoon,Kim, Jungyo 대한생물정신의학회 2017 생물정신의학 Vol.24 No.2

Shift workers experience a disruption in the circadian sleep-wake rhythm, which brings upon adverse health effects such as fatigue, insomnia and decreased sleep quality. Moreover, shift work has deleterious effects on both work productivity and safety. In this review, we present a brief overview of the current literature on the consequences of shift work, especially focusing on attention-associated cognitive decline and related behavioral changes. We searched two electronic databases, PubMed and RISS, using key search terms related to cognitive domains, deleterious effects, and shift work. Twenty studies were eligible for the final review. The consequences of shift work can be classified into the following three categories extracted from the literature review : 1) work accidents ; 2) commuting accidents such as car accidents that occur on the way to and from work ; and 3) attendance management at work (i.e., absenteeism, tardiness, and unscheduled early departure). These cognitive and behavioral consequences of shift work were also found to be associated with sleep disorders in shift workers. Thus, improvements in the shift work system are necessary in order to enhance workers' health conditions, work productivity, and safety.