Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and α-synuclein aggregation.
Abstract
Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes β-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending...
Source: exp Mol Med - April 1, 2015 Category: Molecular Biology Authors: Bae EJ, Yang NY, Lee C, Lee HJ, Kim S, Sardi SP, Lee SJ Tags: Exp Mol Med Source Type: research
Analyses of the TCR repertoire of MHC class II-restricted innate CD4(+) T cells.
Abstract
Analysis of the T-cell receptor (TCR) repertoire of innate CD4(+) T cells selected by major histocompatibility complex (MHC) class II-dependent thymocyte-thymocyte (T-T) interaction (T-T CD4(+) T cells) is essential for predicting the characteristics of the antigens that bind to these T cells and for distinguishing T-T CD4(+) T cells from other types of innate T cells. Using the TCR(mini) Tg mouse model, we show that the repertoire of TCRα chains in T-T CD4(+) T cells was extremely diverse, in contrast to the repertoires previously described for other types of innate T cells. The TCRα chain sequ...
Source: exp Mol Med - April 1, 2015 Category: Molecular Biology Authors: Kang BH, Min HS, Lee YJ, Choi B, Kim EJ, Lee J, Kim JR, Cho KH, Kim TJ, Jung KC, Park SH Tags: Exp Mol Med Source Type: research
Euodia sutchuenensis Dode extract stimulates osteoblast differentiation via Wnt/β-catenin pathway activation.
This study shows that ESD extract stimulates osteoblast differentiation via the Wnt/β-catenin pathway and enhances murine calvarial bone formation ex vivo.
PMID: 25792220 [PubMed - in process] (Source: exp Mol Med)
Source: exp Mol Med - March 22, 2015 Category: Molecular Biology Authors: Hwang JH, Cha PH, Han G, Bach TT, Min do S, Choi KY Tags: Exp Mol Med Source Type: research
Special issue on neurodegenerative diseases and their therapeutic approaches.
PMID: 25766615 [PubMed - as supplied by publisher] (Source: exp Mol Med)
Source: exp Mol Med - March 16, 2015 Category: Molecular Biology Authors: Kim J, Mook-Jung I Tags: Exp Mol Med Source Type: research
Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.
Abstract
Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and t...
Source: exp Mol Med - March 16, 2015 Category: Molecular Biology Authors: Ciechanover A, Kwon YT Tags: Exp Mol Med Source Type: research
Sleep, circadian rhythms, and the pathogenesis of Alzheimer Disease.
Abstract
Disturbances in the sleep-wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep-wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep-wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, th...
Source: exp Mol Med - March 16, 2015 Category: Molecular Biology Authors: Musiek ES, Xiong DD, Holtzman DM Tags: Exp Mol Med Source Type: research
Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome.
Abstract
Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alar...
Source: exp Mol Med - March 16, 2015 Category: Molecular Biology Authors: Kim B, Feldman EL Tags: Exp Mol Med Source Type: research
The role of mitochondrial DNA mutation on neurodegenerative diseases.
Abstract
Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.
PMID: 25766619 [PubMed - as...
Source: exp Mol Med - March 16, 2015 Category: Molecular Biology Authors: Cha MY, Kim DK, Mook-Jung I Tags: Exp Mol Med Source Type: research
Stem cell therapy for Alzheimer's disease and related disorders: current status and future perspectives.
Abstract
Underlying cognitive declines in Alzheimer's disease (AD) are the result of neuron and neuronal process losses due to a wide range of factors. To date, all efforts to develop therapies that target specific AD-related pathways have failed in late-stage human trials. As a result, an emerging consensus in the field is that treatment of AD patients with currently available drug candidates might come too late, likely as a result of significant neuronal loss in the brain. In this regard, cell-replacement therapies, such as human embryonic stem cell- or induced pluripotent stem cell-derived neural cells,...
Source: exp Mol Med - March 16, 2015 Category: Molecular Biology Authors: Tong LM, Fong H, Huang Y Tags: Exp Mol Med Source Type: research
Oligoadenylate synthase-like (OASL) proteins: dual functions and associations with diseases.
Abstract
The study of antiviral pathways to reveal methods for the effective response and clearance of virus is closely related to understanding interferon (IFN) signaling and its downstream target genes, IFN-stimulated genes. One of the key antiviral factors induced by IFNs, 2'-5' oligoadenylate synthase (OAS), is a well-known molecule that regulates the early phase of viral infection by degrading viral RNA in combination with RNase L, resulting in the inhibition of viral replication. In this review, we describe OAS family proteins from a different point of view from that of previous reviews. We discuss n...
Source: exp Mol Med - March 9, 2015 Category: Molecular Biology Authors: Choi UY, Kang JS, Hwang YS, Kim YJ Tags: Exp Mol Med Source Type: research
Scoparone interferes with STAT3-induced proliferation of vascular smooth muscle cells.
Abstract
Scoparone, which is a major constituent of Artemisia capillaries, has been identified as an anticoagulant, hypolipidemic, vasorelaxant, anti-oxidant and anti-inflammatory drug, and it is used for the traditional treatment of neonatal jaundice. Therefore, we hypothesized that scoparone could suppress the proliferation of VSMCs by interfering with STAT3 signaling. We found that the proliferation of these cells was significantly attenuated by scoparone in a dose-dependent manner. Scoparone markedly reduced the serum-stimulated accumulation of cells in the S phase and concomitantly increased the propo...
Source: exp Mol Med - March 9, 2015 Category: Molecular Biology Authors: Park S, Kim JK, Oh CJ, Choi SH, Jeon JH, Lee IK Tags: Exp Mol Med Source Type: research
β-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells.
In this study, we found that the level of β-TrCP1 is downregulated by various protein kinase inhibitors in triple-negative breast cancer (TNBC) cells. A PI3K/mTOR inhibitor PI-103 reduced the level of β-TrCP1 in a wide range of TNBC cells in a proteasome-dependent manner. Concomitantly, the levels of c-Myc and cyclin E were also downregulated by PI-103. PI-103 reduced the phosphorylation of β-TrCP1 prior to its degradation. In addition, knockdown of β-TrCP1 inhibited the proliferation of TNBC cells. We further identified that pharmacological inhibition of mTORC2 was sufficient to reduce the β-TrCP1 and c-Myc levels. T...
Source: exp Mol Med - March 2, 2015 Category: Molecular Biology Authors: Yi YW, Kang HJ, Bae EJ, Oh S, Seong YS, Bae I Tags: Exp Mol Med Source Type: research
Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.
This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1...
Source: exp Mol Med - February 25, 2015 Category: Molecular Biology Authors: Kim SJ, Ho Hur J, Park C, Kim HJ, Oh GS, Lee JN, Yoo SJ, Choe SK, So HS, Lim DJ, Moon SK, Park R Tags: Exp Mol Med Source Type: research
Subdominant H60 antigen-specific CD8 T-cell response precedes dominant H4 antigen-specific response during the initial phase of allogenic skin graft rejection.
Abstract
In allogeneic transplantation, including the B6 anti-BALB.B settings, H60 and H4 are two representative dominant minor histocompatibility antigens that induce strong CD8 T-cell responses. With different distribution patterns, H60 expression is restricted to hematopoietic cells, whereas H4 is ubiquitously expressed. H60-specific CD8 T-cell response has been known to be dominant in most cases of B6 anti-BALB.B allo-responses, except in the case of skin transplantation. To understand the mechanism underlying the subdominance of H60 during allogeneic skin transplantation, we investigated the dynamics ...
Source: exp Mol Med - February 15, 2015 Category: Molecular Biology Authors: Yoo KI, Jeon JY, Ryu SJ, Nam G, Youn H, Choi EY Tags: Exp Mol Med Source Type: research
Understanding of molecular mechanisms in natural killer cell therapy.
Abstract
Cancer cells and the immune system are closely related and thus influence each other. Although immune cells can suppress cancer cell growth, cancer cells can evade immune cell attack via immune escape mechanisms. Natural killer (NK) cells kill cancer cells by secreting perforins and granzymes. Upon contact with cancer cells, NK cells form immune synapses to deliver the lethal hit. Mature NK cells are differentiated from hematopoietic stem cells in the bone marrow. They move to lymph nodes, where they are activated through interactions with dendritic cells. Interleukin-15 (IL-15) is a key molecule ...
Source: exp Mol Med - February 15, 2015 Category: Molecular Biology Authors: Yoon SR, Kim TD, Choi I Tags: Exp Mol Med Source Type: research
