Most anthropoid primates are slow to develop, their offspring are mostly single births, and the interbirth intervals are long. To maintain a stable population, parents must live long enough to sustain the serial production of a sufficient number of young to replace themselves while allowing for the death of offspring before they can reproduce. However, in many species there is a large differential between the sexes in the care provided to offspring. Therefore, we hypothesize that in slowly developing species with single births, the sex that bears the greater burden in the care of offspring will tend to survive longer. Males are incapable of gestating infants and lactating, but in several species fathers carry their offspring for long periods. We predict that females tend to live longer than males in the species where the mother does most or all of the care of offspring, that there is no difference in survival between the sexes in species in which both parents participate about equally in infant care, and that in the species where the father does a greater amount of care than the mother, males tend to live longer. The hypothesis is supported by survival data for males and females in anthropoid primate species.
TP53 is a tumor suppressor gene which is commonly mutated in various cancers including breast cancer. Alterations in the gene lead to an altered expression of various genes that are directly or indirectly under the transcriptional control of p53. This results in malfunctioning of DNA damage repair pathways, cell-cycle arrest, chromatin remodeling and apoptosis. Different mutations in TP53 gene have been reported in different ethnic groups and exon 4 and intron 3 are reported to be frequently mutated in breast cancer patients especially triplenegative breast cancer. Increased global burden of TP53 mutated breast tumors has paved the path for various therapies targeting p53/TP53. Numerous molecules including nutilins, MI series, RO5693, PRIMA-1, RITA, etc. have been developed. Majority of these restore p53/TP53 function by targeting negative regulators of p53/TP53, wtp53/TP53 (wild-type) and mtp53/TP53 (mutant). Most of these molecules are in the preclinical phase except for two APR-246 and COTI-2 that have progressed to clinical trials. The current review has been compiled with an aim to give an overview of mutations in p53 across various ethnic groups, the effect of these alterations on TP53 function and the therapeutic strategies developed till date targeting p53/TP53 especially in breast cancer.
Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson’s disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggregate is still unclear. We report here that UCHL1 undergoes S-nitrosylation in vitro and rotenone induced PD mouse model. The preferential nitrosylation in the Cys 90, Cys 152 and Cys 220 has been observed which alters the catalytic activity and structural stability. We show here that nitrosylation induces structural instability and produces amorphous aggregate, which provides a nucleation to the native α-synuclein for faster aggregation. Our findings provide a new link between UCHL1-nitrosylation and PD pathology.
Parkinson's disease (PD) is a multifactorial malady and the second most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in the midbrain. A hallmark of PD pathology is the formation of intracellular protein inclusions, termed Lewy bodies (LBs). Recent MS studies have shown that OTU deubiquitinase ubiquitin aldehyde-binding 1 (OTUB1), a deubiquitinating enzyme of the OTU family, is enriched together with α-synuclein in LBs from individuals with PD and is also present in amyloid plaques associated with Alzheimer's disease. In the present study, using mammalian cell cultures and a PD mouse model, along with CD spectroscopy, atomic force microscopy, immunofluorescence-based imaging, and various biochemical assays, we demonstrate that after heat-induced protein aggregation, OTUB1 reacts strongly with both anti-A11 and anti-osteocalcin antibodies, detecting oligomeric, prefibrillar structures or fibrillar species of amyloidogenic proteins, respectively. Further, recombinant OTUB1 exhibited high thioflavin-T and Congo red binding and increased β-sheet formation upon heat induction. The oligomeric OTUB1 aggregates were highly cytotoxic, characteristic of many amyloid proteins. OTUB1 formed inclusions in neuronal cells and co-localized with thioflavin S and with α-synuclein during rotenone-induced stress. It also co-localized with the disease-associated variant pS129-α-synuclein in rotenone-exposed mouse brains. Interestingly, OTUB1 aggregates were also associated with severe cytoskeleton damage, rapid internalization inside the neuronal cells, and mitochondrial damage, all of which contribute to neurotoxicity. In conclusion, the results of our study indicate that OTUB1 may contribute to LB pathology through its amyloidogenic properties.
DJ-1 is a deglycase enzyme which exhibits a redox-sensitive chaperone-like activity. The partially oxidized state of DJ-1 is active in inhibiting the aggregation of α-synuclein, a key protein associated with Parkinson’s disease. The underlying molecular mechanism behind α-synuclein aggregation inhibition remains unknown. Here we report that the partially oxidized DJ-1 possesses an adhesive surface which sequesters α-synuclein monomers and blocks the early stages of α-synuclein aggregation and also restricts the elongation of α-synuclein fibrils. DJ-1 remodels mature α-synuclein fibrils into heterogeneous toxic oligomeric species. The remodeled fibers show loose surface topology due to a decrease in elastic modulus and disrupt membrane architecture, internalize easily and induce aberrant nitric oxide release. Our results provide a mechanism by which partially oxidized DJ-1 counteracts α-synuclein aggregation at initial stages of aggregation and provide evidence of a deleterious effect of remodeled α-synuclein species generated by partially oxidized DJ-1.
α-Synuclein, a major constituent of proteinaceous inclusions named Lewy body, has been shown to be released and taken up by cells, which may facilitate its progressive pathological spreading and neuronal cell death in Parkinson's disease. However, the pathophysiological effect and signaling cascade initiated by extracellular α-synuclein in cellular milieu are not well understood. Herein we have investigated the perturbations induced by low molecular weight α-synuclein and different types of α-synuclein oligomers in the neuroblastoma SH-SY5Y cells. Atomic force microscopy studies have revealed formation of nanopores and enhanced roughness in the cell surface leading to membrane disruption. The damaged membrane allows altered ionic homeostasis leading to activation of nitric oxide synthase (NOS) machinery releasing burst of nitric oxide. The elevated levels of nitric oxide induces S-nitrosylation of key proteins like Actin, DJ-1, HSP70 UCHL1, Parkin, and GAPDH that alter cytoskeletal network, protein folding machinery, ubiquitin proteasome system inducing apoptosis.
BackgroundMicroalgae grown under different nutrient deficient conditions present a good source of natural lipids with applications for several types of biofuels. The expression of acetyl-CoA carboxylase gene can further provide an insight to the mechanisms leading to enhanced lipid production under such stresses. In this study, two nutrients viz. nitrogen and phosphorus were modulated to see its effect on lipid productivity in selected cyanobacteria and its correlation with Accase followed by molecular dynamics simulation.ResultsSelected cyanobacteria viz. Oscillatoria sp. (SP8), Anabaena sp. (SP12), Anabaena sp. (SP13), Microcoleus sp. (SP18), and Nostoc sp. (SP20) varied in their ability to accumulate lipids which ranged from a lowest of 0.13% in Anabaena sp. (SP13) to the maximum of 7.24% in Microcoleus sp. (SP18). Microcoleus sp. (SP18) also recorded highest lipid accumulation at both N (6 mM NaNO3) and P (0.20 mM K2HPO4) limiting conditions. The overall expression of accD was found to be upregulated in both Oscillatoria sp. (SP8) and Microcoleus sp. (SP18) for all nitrogen concentrations but was differentially regulated with both positive and negative induction under phosphorus stress conditions. Maximum induction was observed in Microcoleus sp. (SP18) at 0.20 mM K2HPO4. The obtained 3D structure of SP8 protein (21.8 kDa) showed six alpha helices, while SP18 protein (16.7 kDa) exhibited four alpha helices and four beta sheets. The phi (ϕ)/psi(ψ) angles of the amino acid residues observed in Ramachandran plot analysis showed that both SP8 and SP18 proteins were highly stable with more than 90% amino acids in allowed regions. The molecular dynamics simulation results also indicated the stability of ligand-bound protein complexes.ConclusionIt has been demonstrated that cyanobacterial isolates are affected differently by nutrient limitation leading to variation in their lipid productivity. The same has been revealed by the behavior of accD gene expression which was regulated more by nutrients concentrations rather than the organism. However, the ligand-bound protein complexes were stable throughout MD simulations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13068-017-0776-2) contains supplementary material, which is available to authorized users.
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