Epigenetic regulons in Alzheimer's disease.

Alzheimer's disease is one of the most prevalent forms of dementia that occur genetically or sporadically (with increasing age) in the population of 65 years and above. The pathological hallmarks of AD include the formation of extracellular senile plaques of amyloid beta peptides 42 (Aß42) and intracellular neurofibrillary tangles associated with hyperphosphorylated tau protein. AD has been reported as an outcome of multiple probabilistic factors such as age, lifestyle, oxidative stress, inflammation, insulin resistance, mitochondrial dysfunction, and epigenetics. Epigenetics are heritable changes in gene expression that give a phenotype without altering the DNA sequences. Epigenetic mechanisms include DNA methylation, hydroxymethylation, histone modifications, regulation of miRNAs and long non-coding RNAs, which are reported to be dysregulated in AD. Further, epigenetic mechanisms have been shown as a key player as they regulate memory development, where DNA methylation and post-translational modifications of histone tails are the prime epigenetic markers. Also, alterations of AD-related genes cause pathogenesis on the transcriptional level. In the current chapter, we summarize the role of epigenetics in the onset and progression of AD and the use of epigenetic therapeutics to ameliorate the constraints of AD.

Epigenetic control of heredity.

Epigenetics is the field of science that deals with the study of changes in gene function that do not involve changes in DNA sequence and are heritable while epigenetics inheritance is the process of transmission of epigenetic modifications to the next generation. It can be transient, intergenerational, or transgenerational. There are various epigenetic modifications involving mechanisms such as DNA methylation, histone modification, and noncoding RNA expression, all of which are inheritable. In this chapter, we summarize the information on epigenetic inheritance, its mechanism, inheritance studies on various organisms, factors affecting epigenetic modifications and their inheritance, and the role of epigenetic inheritance in the heritability of diseases.

Aging: Epigenetic modifications.

Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.

Synthetic receptors in medicine.

Cellular signaling is controlled by ligand receptor interaction and subsequent biochemical changes inside the cell. Manipulating receptors as per need that can be a strategy to alter the disease pathologies in various conditions. With recent advances in synthetic biology, now it is possible to engineer the artificial receptor "synthetic receptors." Synthetic receptors are the engineering receptors that have potential to alter the disease pathology by altering/manipulating the cellular signaling. Several synthetic receptors are being engineered that have shown positive regulation in several disease conditions. Thus, synthetic receptor-based strategy opens a new avenue in the medical field to cope up with various health issues. The current chapter summarizes updated information about the synthetic receptors and their applications in the medical field.

Sirtuins, a key regulator of ageing and age-related neurodegenerative diseases.

Sirtuins are Nicotinamide Adenine Dinucleotide (NAD+) dependent class ІΙΙ histone deacetylases enzymes (HDACs) present from lower to higher organisms such as bacteria (Sulfolobus solfataricus L. major), yeasts (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), humans (Homo sapiens sapiens), even in plants such as rice (Oryza sativa), thale cress (Arabidopsis thaliana), vine (Vitis vinifera L.) tomato (Solanum lycopersicum). Sirtuins play an important role in the regulation of various vital cellular functions during metabolism and ageing. It also plays a neuroprotective role by modulating several biological pathways such as apoptosis, DNA repair, protein aggregation, and inflammatory processes associated with ageing and neurodegenerative diseases. In this review, we have presented an updated Sirtuins and its role in ageing and age-related neurodegenerative diseases (NDDs). Further, this review also describes the therapeutic potential of Sirtuins and the use of Sirtuins inhibitor/activator for altering the NDDs disease pathology.

Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases.

Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca2+ homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.

Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aß42 and Appl) in Drosophila melanogaster.

Miro (mitochondrial Rho GTPases), a mitochondrial outer membrane protein, facilitates mitochondrial axonal transport along the microtubules to facilitate neuronal function. It plays an important role in regulating mitochondrial dynamics (fusion and fission) and cellular energy generation. Thus, Miro might be associated with the key pathologies of several neurodegenerative diseases (NDs) including Alzheimer's disease (AD). In the present manuscript, we have demonstrated the possible genetic interaction between Miro and AD-related genes such as Tau, Aß42 and Appl in Drosophila melanogaster Ectopic expression of Tau, Aß42 and Appl induced a rough eye phenotype, defects in phototaxis and climbing activity, and shortened lifespan in the flies. In our study, we have observed that overexpression of Miro improves the rough eye phenotype, behavioral activities (climbing and phototaxis) and ATP level in AD model flies. Further, the improvement examined in AD-related phenotypes was correlated with decreased oxidative stress, cell death and neurodegeneration in Miro overexpressing AD model flies. Thus, the obtained results suggested that Miro genetically interacts with AD-related genes in Drosophila and has the potential to be used as a therapeutic target for the design of therapeutic strategies for NDs.This article has an associated First Person interview with the first author of the paper.

A Forward Genetic Approach to Mapping a P-Element Second Site Mutation Identifies DCP2 as a Novel Tumor Suppressor in Drosophila melanogaster.

The use of transposons to create mutations has been the cornerstone of Drosophila genetics in the past few decades. Second-site mutations caused by transpositions are often devoid of transposons and thereby affect subsequent analyses. In a P-element mutagenesis screen, a second site mutation was identified on chromosome 3, wherein the homozygous mutants exhibit classic hallmarks of tumor suppressor mutants, including brain tumor and lethality; hence the mutant line was initially named as lethal (3) tumorous brain [l(3)tb]. Classical genetic approaches relying on meiotic recombination and subsequent complementation with chromosomal deletions and gene mutations mapped the mutation to CG6169, the mRNA decapping protein 2 (DCP2), on the left arm of the third chromosome (3L). Thus the mutation was renamed as DCP2l(3)tb Fine mapping of the mutation further identified the presence of a Gypsy-LTR like sequence in the 5'UTR coding region of DCP2, along with the expansion of the adjacent upstream intergenic AT-rich sequence. The mutant phenotypes are rescued by the introduction of a functional copy of DCP2 in the mutant background, thereby establishing the causal role of the mutation and providing a genetic validation of the allelism. With the increasing repertoire of genes being associated with tumor biology, this is the first instance of mRNA decapping protein being implicated in Drosophila tumorigenesis. Our findings, therefore, imply a plausible role for the mRNA degradation pathway in tumorigenesis and identify DCP2 as a potential candidate for future explorations of cell cycle regulatory mechanisms.

Mitochondrial dynamics, a key executioner in neurodegenerative diseases.

Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well-studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions.

Heat shock protein-70 (Hsp-70) suppresses paraquat-induced neurodegeneration by inhibiting JNK and caspase-3 activation in Drosophila model of Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders with limited clinical interventions. A number of epidemiological as well as case-control studies have revealed an association between pesticide exposure, especially of paraquat (PQ) and occurrence of PD. Hsp70, a molecular chaperone by function, has been shown as one of the modulators of neurological disorders. However, paucity of information regarding the protective role of Hsp70 on PQ-induced PD like symptoms led us to hypothesize that modulation of hsp70 expression in the dopaminergic neurons would improve the health of these cells. We took advantage of Drosophila, which is a well-established model for neurological research and also possesses genetic tools for easy manipulation of gene expression with limited ethical concern. Over-expression of hsp70 was found to reduce PQ-induced oxidative stress along with JNK and caspase-3 mediated dopaminergic neuronal cell death in exposed organism. Further, anti-apoptotic effect of hsp70 was shown to confer better homeostasis in the dopaminergic neurons of PQ-exposed organism as evidenced by their improved locomotor performance and survival. The study has merit in the context of human concern since we observed protection of dopaminergic neurons in PQ-exposed organism by over-expressing a human homologue of hsp70, HSPA1L, in these cells. The effect was parallel to that observed with Drosophila hsp70. These findings reflect the potential therapeutic applicability of hsp70 against PQ-induced PD like symptoms in an organism.