Saurabh Kumar Jha

Tau Phosphorylation, Molecular Chaperones, and Ubiquitin E3 Ligase: Clinical Relevance in Alzheimer's Disease

Alzheimers disease (AD) is characterized by dementia, cognitive disabilities, and tauopathy. Tau is a microtubule associated protein that helps maintain the neuronal network. While phosphorylation of tau protein causes disruption of the microtubular network, dephosphorylation allows reconstitution of the microtubule network. Several kinases, e.g., MARK, MAPK, and protein kinase C, are known to hyperphosphorylate tau, leading to disruption of the microtubular network and formation of neurofibrillary tangles (NFTs), which are further glycosylated, glycated, and have lipid peroxide adducts that impair the neuronal transport system and affect memory formation and retention. Moreover, intracerebral administration of amyloid-β oligomers causes hyperphosphorylation of tau, but whether it is involved in the formation of NFTs is still unclear. Further, amyloid burden activates AMP-activated protein kinase that increases phosphorylation of tau at position Ser262/Ser356 and Ser396. Several phosphatases are present at low levels in AD brains indicating that their down regulation results in abnormal hyperphosphorylation of tau. However, evidence strengthens a possible link between tau phosphorylation and molecular chaperone mediated tau metabolism for the clearance of toxic tau accumulation and has a crucial role in tauopathy. Furthermore, accumulation of phosphorylated tau protein and the possibility of removing the toxic phosphorylated tau protein from the milieu indicates that the chaperone interacts with phosphorylated tau and promotes its degradation. For instance, Hsp90 and cdc37 regulate tau stability and phosphorylation dynamics whereas Hsp27 is able to modulate neuronal plasticity, while 14-3-3 is involved in the interaction of tau with small HSPs. Hsp70 ATPase acts as a modulator in AD therapeutics while Hsc70 rapidly engages tau after microtubular destabilization. Herein, we highlight the various causes of tauopathy and HSP-E3 ligase mediated therapeutics in AD.

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration.

Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimers disease (AD), Parkinsons disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca2+ release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

Ion Channels in Neurological Disorders

The convergent endeavors of the neuroscientist to establish a link between clinical neurology, genetics, loss of function of an important protein, and channelopathies behind neurological disorders are quite intriguing. Growing evidence reveals the impact of ion channels dysfunctioning in neurodegenerative disorders (NDDs). Many neurological/neuromuscular disorders, viz, Alzheimers disease, Parkinsons disease, Huntingtons disease, multiple sclerosis, amyotrophic lateral sclerosis, and age-related disorders are caused due to altered function or mutation in ion channels. To maintain cell homeostasis, ion channels are playing a crucial role which is a large transmembrane protein. Further, these channels are important as it determines the membrane potential and playing critically in the secretion of neurotransmitter. Behind NDDs, losses of pathological proteins and defective ion channels have been reported and are found to aggravate the disease symptoms. Moreover, ion channel dysfunctions are eliciting a range of symptoms, including memory loss, movement disabilities, neuromuscular sprains, and strokes. Since the possible mechanistic role played by aberrant ion channels, their receptor and associated factors in neurodegeneration remained elusive; therefore, it is a challenging task for the neuroscientist to implement the therapeutics for targeting NDDs. This chapter reviews the potential role of the ion channels in membrane physiology and brain homeostasis, where ion channels and their associated factors have been characterized with their functional consequences in neurological diseases. Moreover, mechanistic role of perturbed ion channels has been identified in various NDDs, and finally, ion channel modulators have been investigated for their therapeutic intervention in treating common NDDs.

Comparative study of anti-angiogenic activities of luteolin, lectin and lupeol biomolecules.

AbstractBackgroundAngiogenesis is a hallmark feature in the initiation, progression and growth of tumour. There are various factors for promotion of angiogenesis on one hand and on the other hand, biomolecules have been reported to inhibit cancer through anti-angiogenesis mechanism. Biomolecules, for instance, luteolin, lectin and lupeol are known to suppress cancer. This study aims to compare and evaluate the biomolecule(s) like luteolin, lupeol and lectin on CAM assay and HT-29 cell culture to understand the efficacy of these drugs.MethodThe biomolecules have been administered on CAM assay, HT-29 cell culture, cell migration assay. Furthermore, bioinformatics analysis of the identified targets of these biomolecules have been performed.ResultLuteolin has been found to be better in inhibiting angiogenesis on CAM assay in comparison to lupeol and lectin. In line with this study when biomolecules was administered on cell migration assay via scratch assay method. We provided evidence that Luteolin was again found to be better in inhibiting HT-29 cell migration. In order to identify the target sites of luteolin for inhibition, we used software analysis for identifying the best molecular targets of luteolin. Using software analysis best target protein molecule of these biomolecules have been identified. VEGF was found to be one of the target of luteolin. Studies have found several critical point mutation in VEGF A, B and C. Hence docking analysis of all biomolecules with VEGFR have been performed. Multiple allignment result have shown that the receptors are conserved at the docking site.ConclusionTherefore, it can be concluded that luteolin is not only comparatively better in inhibiting blood vessel in CAM assay, HT-29 cell proliferation and cell migration assay rather the domain of VEGFR is conserved to be targeted by luteolin, lupeol and lectin.

Re-expression of cell cycle markers in aged neurons and muscles: Whether cells should divide or die?

Emerging evidence revealed that abrogated cell cycle entry into highly differentiated mature neurons and muscles is having detrimental consequences in response to cell cycle checkpoints disruption, altered signaling cascades, pathophysiological and external stimuli, for instance, Aβ, Parkin, p-tau, α-synuclein, impairment in TRK, Akt/GSK3β, MAPK/Hsp90, and oxidative stress. These factors, reinitiate undesired cell division by triggering new DNA synthesis, replication, and thus exquisitely forced mature cell to enter into a disturbed and vulnerable state that often leads to death as reported in many neuro- and myodegenerative disorders. A pertinent question arises how to reverse this unwanted pathophysiological phenomenon is attributed to the usage of cell cycle inhibitors to prevent the degradation of crucial cell cycle arresting proteins, cyclin inhibitors, chaperones and E3 ligases. Herein, we identified the major culprits behind the forceful cell cycle re-entry, elucidated the cyclin re-expression based on disturbed signaling mechanisms in neuromuscular degeneration together with plausible therapeutic strategies.

Epigenetics and Angiogenesis in Cancer

Cancer is a most common and lethal disease in which certain cells in our body grow in an uncontrolled way. The growth of new vascular network is essential for sustained growth of tumor to adequately supply nutrients and oxygen. These requirements are mainly fulfilled by formation of fresh blood vessels. Angiogenesis plays a pivotal role in various physiological conditions within the human body, including, embryonic development and tissue repair after trauma or surgery. Angiogenesis is a hallmark feature of cancer, inflammatory diseases, and wound healing. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of gene especially through small RNAs. Epigenetic modification of tumor cells includes diverse reinforcing and converging signals, including histone modifications, DNA methylation, and non-coding RNAs. This chapter is focused on highlighting the role of angiogenesis in vasculogenesis process and epigenetic modifications in cancer progression. Moreover, we reported the importance of various angiogenic factors and their epigenetic modifications together with a novel therapeutic window towards the treatment of most common cancers using epigenetic regulators.