ER-mitochondria signaling in Parkinson's disease Gómez-Suaga, Patricia; Bravo-San Pedro, José M; González-Polo, Rosa A ...
Cell death & disease,
03/2018, Letnik:
9, Številka:
3
Journal Article
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Mitochondria form close physical contacts with a specialized domain of the endoplasmic reticulum (ER), known as the mitochondria-associated membrane (MAM). This association constitutes a key ...signaling hub to regulate several fundamental cellular processes. Alterations in ER-mitochondria signaling have pleiotropic effects on a variety of intracellular events resulting in mitochondrial damage, Ca
dyshomeostasis, ER stress and defects in lipid metabolism and autophagy. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases. Furthermore, increasing evidence highlights that ER-mitochondria signaling contributes to these diseases, including Parkinson's disease (PD). PD is the second most common neurodegenerative disorder, for which effective mechanism-based treatments remain elusive. Several PD-related proteins localize at mitochondria or MAM and have been shown to participate in ER-mitochondria signaling regulation. Likewise, PD-related mutations have been shown to damage this signaling. Could ER-mitochondria associations be the link between pathogenic mechanisms involved in PD, providing a common mechanism? Would this provide a pharmacological target for treating this devastating disease? In this review, we aim to summarize the current knowledge of ER-mitochondria signaling and the recent evidence concerning damage to this signaling in PD.
The main purpose of this review was to systematically analyze the literature concerning studies which have investigated muscle activation when performing the Deadlift exercise and its variants. This ...study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement (PRISMA). Original studies from inception until March 2019 were sourced from four electronic databases including PubMed, OVID, Scopus and Web of Science. Inclusion criteria were as follows: (a) a cross-sectional or longitudinal study design; (b) evaluation of neuromuscular activation during Deadlift exercise or variants; (c) inclusion of healthy and trained participants, with no injury issues at least for six months before measurements; and (d) analyzed "sEMG amplitude", "muscle activation" or "muscular activity" with surface electromyography (sEMG) devices. Major findings indicate that the biceps femoris is the most studied muscle, followed by gluteus maximus, vastus lateralis and erector spinae. Erector spinae and quadriceps muscles reported greater activation than gluteus maximus and biceps femoris muscles during Deadlift exercise and its variants. However, the Romanian Deadlift is associated with lower activation for erector spinae than for biceps femoris and semitendinosus. Deadlift also showed greater activation of the quadriceps muscles than the gluteus maximus and hamstring muscles. In general, semitendinosus muscle activation predominates over that of biceps femoris within hamstring muscles complex. In conclusion 1) Biceps femoris is the most evaluated muscle, followed by gluteus maximus, vastus lateralis and erector spinae during Deadlift exercises; 2) Erector spinae and quadriceps muscles are more activated than gluteus maximus and biceps femoris muscles within Deadlift exercises; 3) Within the hamstring muscles complex, semitendinosus elicits slightly greater muscle activation than biceps femoris during Deadlift exercises; and 4) A unified criterion upon methodology is necessary in order to report reliable outcomes when using surface electromyography recordings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease ...mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S
leucine-rich repeat kinase 2
(LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S
LRRK2
mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S
LRRK2
mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect.
Although oxidative stress is fundamental to the etiopathology of Parkinson disease, the signaling molecules involved in transduction after oxidant exposure to cell death are ill-defined, thus making ...it difficult to identify molecular targets of therapeutic relevance. We have addressed this question in human dopaminergic neuroblastoma SH-SY5Y cells exposed to the parkinsonian toxin paraquat (PQ). This toxin elicited a dose-dependent increase in reactive oxygen species and cell death that correlated with activation of ASK1 and the stress kinases p38 and JNK. The relevance of these kinases in channeling PQ neurotoxicity was demonstrated with the use of interference RNA for ASK1 and two well-established pharmaceutical inhibitors for JNK and p38. The toxic effect of PQ was substantially attenuated by preincubation with vitamin E, blocking ASK1 pathways and preventing oxidative stress and cell death. In a search for a physiological pathway that might counterbalance PQ-induced ASK1 activation, we analyzed the role of the transcription factor Nrf2, master regulator of redox homeostasis, and its target thioredoxin (Trx), which binds and inhibits ASK1. Trx levels were undetectable in Nrf2-deficient mouse embryo fibroblasts (MEFs), whereas they were constitutively high in Keap1-deficient MEFs as well as in SH-SY5Y cells treated with sulforaphane (SFN). Consistent with these data, Nrf2-deficient MEFs were more sensitive and Keap1-deficient MEFs and SH-SY5Y cells incubated with SFN were more resistant to PQ-induced cell death. This study identifies ASK1/JNK and ASK1/p38 as two critical pathways involved in the activation of cell death under oxidative stress conditions and identifies the Nrf2/Trx axis as a new target to block these pathways and protect from oxidant exposure such as that found in Parkinson and other neurodegenerative diseases.
The Monopodal Squat, Forward Lunge and Lateral Step-Up exercises are commonly performed with one's own body weight for rehabilitation purposes. However, muscle activity evaluated using surface ...electromyography has never been analyzed among these three exercises. Therefore, the objectives of the present study were to evaluate the amplitude of the EMG activity of the gluteus medius, gluteus maximus, biceps femoris, vastus lateralis, vastus medialis and rectus femoris muscles in participants performing the Lateral Step-Up, Forward Lunge and Monopodal Squat exercises. A total of 20 physically active participants (10 men and 10 women) performed 5 repetitions at 60% (5 repetition maximum) in each of the evaluated exercises. The EMG amplitude was calculated in percentage of the maximum voluntary contraction. The Monopodal Squat exercise showed a higher EMG activity (p ≤ 0.001) in relation to the Lateral Step-Up and Forward Lunge exercises in all of the evaluated muscles (d > 0.6) except for the rectus femoris. The three exercises showed significantly higher EMG activity in all of the muscles that were evaluated in the concentric phase in relation to the eccentric one. In the three evaluated exercises, vastus lateralis and vastus medialis showed the highest EMG activity, followed by gluteus medius and gluteus maximus. The Monopodal Squat, Forward Lunge and Lateral Step-Up exercises not only are recommended for their rehabilitation purposes but also should be recommended for performance objectives and strength improvement in the lower limbs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of familial Parkinsonism, and the G2019S mutation of LRRK2 is one of the most prevalent mutations. The deregulation of autophagic ...processes in nerve cells is thought to be a possible cause of Parkinson’s disease (PD). In this study, we observed that G2019S mutant fibroblasts exhibited higher autophagic activity levels than control fibroblasts. Elevated levels of autophagic activity can trigger cell death, and in our study, G2019S mutant cells exhibited increased apoptosis hallmarks compared to control cells. LRRK2 is able to induce the phosphorylation of MAPK/ERK kinases (MEK). The use of 1,4-diamino-2,3-dicyano-1,4-bis2-aminophenylthiobutadiene (U0126), a highly selective inhibitor of MEK1/2, reduced the enhanced autophagy and sensibility observed in G2019S LRRK2 mutation cells. These data suggest that the G2019S mutation induces autophagy via MEK/ERK pathway and that the inhibition of this exacerbated autophagy reduces the sensitivity observed in G2019S mutant cells.
Knowledge management (KM) is a field of research that has gained wide acceptance in the scientific community and management literature. This article presents a bibliometric overview of the academic ...research on KM in the business and management areas. Various bibliometric methods are used to perform this overview, including performance analysis and science mapping of the KM field. The performance analysis uses a series of bibliometric indicators, such as the h-index, productivity and citations. In addition, the VOSviewer software is used to map the bibliographic material. Science mapping uses co-citations and the concurrency of keywords. References were obtained from the Web of Science database. We identified and classified the most relevant research in the field according to journals, articles, authors, institutions and countries. The results show that research in this field has increased significantly in the last ten years and that the USA is the most influential country in all aspects in this field. It is important to consider, however, that science continues to advance in this and in all fields and that data rapidly change over time. Therefore, this paper fulfills an informational role that shows that most of the fundamental research of KM is in business and management areas.
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•A bibliometric overview of research in knowledge management (KM) is presented.•The analysis focuses on documents in the area of business and management.•Our bibliometric involves a performance analysis and a science mapping of KM field.•The work shows a significant increase of knowledge management research.•The United States followed by developed countries leads KM's research extensively.
The role of autophagy as a survival strategy of cells constitutes an emerging topic in the study of the pathogenesis of several diseases with autophagic changes being described in a number of ...age-related neurodegenerative disorders, including Parkinson's disease (PD). Although the etiology of PD is still unknown, both environmental (for example, paraquat exposure) and genetic factors have been investigated as putative causes of the disease. In the latter case, mutations or changes in the protein DJ-1 have been reported to be associated with autosomal recessive, early-onset parkinsonism. In this paper we established a model system to study the involvement of the DJ-1 protein in paraquat-induced autophagy. When human neuroblastoma SH-SY5Y cells were transfected with DJ-1-specific small interfering RNAs and exposed to paraquat, we observed (i) sensitization additive with paraquat-induced apoptotic cell death, (ii) inhibition of the cytoplasmic accumulation of autophagic vacuoles as well as the recruitment of LC3 fusion protein to the vacuoles, (iii) exacerbation of apoptotic cell death in the presence of the autophagy inhibitor 3-methyladenine, and (iv) an increase in mammalian target of rapamycin phosphorylation. Taken together, these findings suggest an active role for DJ-1 in the autophagic response produced by paraquat, providing evidence for the role of PD-related proteins in the autophagic degradation pathway, a factor that should be considered in the design of potential therapies for the treatment of the disease.
Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of ...endoplasmic reticulum (ER) stress, c‐Jun‐N‐terminal kinase (JNK), Akt, and 5′AMP‐activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P‐eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P‐JNK1/2/JNK1/2, Thr172P‐AMPKα, Ser413P‐Foxo3a, Thr308P‐AKt/AKt and Thr32P‐Foxo3a/Foxo3a ratios, and reduction of Ser2481P‐mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim
EL, Beclin‐1, Bcl‐xL, Bcl‐2, autophagy markers, and reduction of myeloid cell leukemia‐1 (Mcl‐1) expression. The progressive increase of CHOP expression, and reduction of Thr308P‐AKt/AKt and Ser473P‐AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim
EL expression and caspase‐3 activity (24 hr). Small interfering‐RNA (si‐RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase‐3 in sorafenib‐treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor‐derived xenograft model. In conclusion, the early sorafenib‐induced ER stress and regulation of JNK and AMPK‐dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK‐CHOP‐dependent rise of Bim
EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim
EL expression profile might also be related to the tight balance between AKt‐ and AMPK‐related signaling leading to Foxo3a‐dependent BIM
EL upregulation.
The early sorafenib‐induced endoplasmic reticulum (ER) stress and regulation of JNK and AMPK‐dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK‐CHOP‐dependent rise of BimEL, which was associated with the shift from autophagy to apoptosis.
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