Polyglutamine disorders: Pathogenesis and potential drug interventions.

Polyglutamine/poly(Q) diseases are a group nine hereditary neurodegenerative disorders caused due to abnormally expanded stretches of CAG trinucleotide in functionally distinct genes. All human poly(Q) diseases are characterized by the formation of microscopically discernable poly(Q) positive aggregates, the inclusion bodies. These toxic inclusion bodies are responsible for the impairment of several cellular pathways such as autophagy, transcription, cell death, etc., that culminate in disease manifestation. Although, these diseases remain largely without treatment, extensive research has generated mounting evidences that various events of poly(Q) pathogenesis can be developed as potential drug targets. The present review article briefly discusses the key events of disease pathogenesis, model system-based investigations that support the development of effective therapeutic interventions against pathogenesis of human poly(Q) disorders, and a comprehensive list of pharmacological and bioactive compounds that have been experimentally shown to alleviate poly(Q)-mediated neurotoxicity. Interestingly, due to the common cause of pathogenesis, all poly(Q) diseases share etiology, thus, findings from one disease can be potentially extrapolated to other poly(Q) diseases as well.

Noncytotoxic WORM Memory Using Lysozyme with Ultrahigh Stability for Transient and Sustainable Electronics Applications.

Biocompatibility and transient nature of electronic devices have been the matter of attention in recent times due to their immense potential for sustainable solutions toward hazardous e-wastes. In order to fulfill the requirement of high-density data-storage devices due to explosive growth in digital data, a resistive switching (RS)-based memory device could be the promising alternative to the present Si-based electronics. In this research work, we employed a biocompatible enzymatic protein lysozyme (Lyso) as the active layer to design a RS memory device having a device structure Au/Lyso/ITO. Interestingly the device showed transient, WORM memory behavior. It has been observed that the WORM memory performance of the device was very good with high memory window (2.78 × 102), data retention (up to 300 min), device yield (∼73.8%), read cyclability, as well as very high device stability (experimentally >700 days, extrapolated to 3000 days). Bias-induced charge trapping followed by conducting filament formation was the key behind such switching behavior. Transient behavior analysis showed that electronic as well as optical behaviors completely disappeared after 10 s dissolution of the device in luke warm water. Cytotoxicity of the as-prepared device was tested by challenging two environmentally derived bacteria, S. aureus and P. aeruginosa, and was found to have no biocidal effects. Hence, the device would cause no harm to the microbial flora when it is discarded. As a whole, this work suggests that Lyso-based WORM memory device could play a key role for the design of transient WORM memory device for sustainable electronic applications.

Targeted upregulation of dMyc restricts JNK-mediated degeneration of dopaminergic neurons in the paraquat-induced Parkinson's disease model of Drosophila.

Parkinson's disease is the second most common neurodegenerative disease characterized by the loss of dopaminergic neurons in the brain. Parkinson's disease has both familial and sporadic cases of origin governed differentially by genetic and/or environmental factors. Different epidemiological studies have proposed an association between the pathogenesis of cancer and Parkinson's disease; however, a precise correlation between these two illnesses could not be established yet. In this study, we examined the disease-modifying property of dmyc (a Drosophila homolog of human cmyc proto-oncogene) in the paraquat-induced sporadic Parkinson's disease model of Drosophila. We report for the first time that targeted upregulation of dMyc significantly restricts paraquat-mediated neurotoxicity. We observed that paraquat feeding reduces the cellular level of dMyc. We further noted that targeted upregulation of dMyc in paraquat-exposed flies mitigates degeneration of dopaminergic neurons by reinstating the aberrantly activated JNK pathway, and this in turn improves the motor performance and survival rate of the flies. Our study provides the first evidence that improved cellular level of dMyc could efficiently minimize the neurotoxic effects of paraquat, which could be beneficial in designing novel therapeutic strategies against Parkinson's disease.

Reinstated Activity of Human Tau-induced Enhanced Insulin Signaling Restricts Disease Pathogenesis by Regulating the Functioning of Kinases/Phosphatases and Tau Hyperphosphorylation in Drosophila.

Tauopathies such as Alzheimer's disease (AD), Frontotemporal dementia, and parkinsonism linked to chromosome 17 (FTDP-17), etc. are characterized by tau hyperphosphorylation and distinguished accumulation of paired helical filaments (PHFs)/or neurofibrillary tangles (NFTs) in a specific-neuronal subset of the brain. Among different reported risk factors, type 2 diabetes (T2D) has gained attention due to its correlation with tau pathogenesis. However, mechanistic details and the precise contribution of insulin pathway in tau etiology is still debatable. We demonstrate that expression of human tau causes overactivation of insulin pathway in Drosophila disease models. We subsequently noted that tissue-specific downregulation of insulin signaling or even exclusive reduction of its growth-promoting sub-branch effectively reinstates the overactivated insulin signaling pathway in human tau expressing cells, which in turn restricts pathogenic tau hyperphosphorylation and aggregate formation. It was further noted that restored tau phosphorylation was achieved due to a reestablished balance between the levels of different kinase(s) (GSK3ß and ERK/P38 MAP kinase) and phosphatase (PP2A). Taken together, our study demonstrates a precise involvement of the insulin pathway and associated molecular events in the pathogenesis of human tauopathies in Drosophila, which will be immensely helpful in developing novel therapeutic options against these devastating human brain disorders. Moreover, our study reveals an interesting link between tau etiology and aberrant insulin signaling, which is a characteristic feature of Type 2 Diabetes.

Effect of long chain fatty acids on the memory switching behavior of tetraindolyl derivatives.

Non-volatile memory devices using organic materials have attracted much attention due to their excellent scalability, fast switching speed, low power consumption, low cost etc. Here, we report both volatile as well as non-volatile resistive switching behavior of p-di[3,3'-bis(2-methylindolyl)methane]benzene (Indole2) and its mixture with stearic acid (SA). Previously, we have reported the bipolar resistive switching (BRS) behavior using 1,4-bis(di(1H-indol-3-yl)methyl)benzene (Indole1) molecules under ambient conditions [Langmuir 37 (2021) 4449-4459] and complementary resistive switching (CRS) behavior when the device was exposed to 353 K or higher temperature [Langmuir 38 (2022) 9229-9238]. However, the present study revealed that when the H of -NH group of Indole1 is replaced by -CH3, the resultant Indole2 molecule-based device showed volatile threshold switching behaviour. On the other hand, when Indole2 is mixed with SA at a particular mole fraction, dynamic evolution of an Au/Indole2-SA/ITO device from volatile to non-volatile switching occurred with very good device stability (>285 days), memory window (6.69 × 102), endurance (210 times), data retention (6.8 × 104 s) and device yield of the order of 78.5%. Trap controlled SCLC as well as electric field driven conduction was the key behind the observed switching behaviour of the devices. In the active layer, trap centers due to the SA network may be responsible for non-volatile characteristics of the device. Observed non-volatile switching may be a potential candidate for write once read many (WORM) memory applications in future.

Glutamine stimulates the S6K/4E-BP branch of insulin signalling pathway to mitigate human poly(Q) disorders in Drosophila disease models.

OBJECTIVE AND METHODS: Since, the S6K/4E-BP sub-pathway can be stimulated by various amino acids; we extended our investigation to examine if oral feeding of amino acids delivers rescue against human poly(Q) toxicity in Drosophila. We utilised Drosophila models of two different poly(Q) disorders to test our hypothesis. Glutamine was fed to the test flies orally mixed in the food. Control and treated flies were then tested for different parameters, such as formation of poly(Q) aggregates and neurodegeneration, to evaluate glutamine's proficiency in mitigating poly(Q) neurotoxicity. RESULTS: Our study, for the first time, reports that glutamine feeding stimulates the growth promoting S6K/4E-BP branch of insulin signalling pathway and restricts pathogenesis of poly(Q) disorders in Drosophila disease models. We noted that glutamine treatment restricts the formation of neurotoxic poly(Q) aggregates and minimises neuronal deaths. Further, glutamine treatment re-establishes the chromatin architecture by improving the histone acetylation which is otherwise compromised in poly(Q) expressing neuronal cells. DISCUSSION: Since, the insulin signalling pathway as well as mechanism of action of glutamine are fairly conserved between human and Drosophila, our finding strongly suggests that glutamine holds immense potential to be developed as an intervention therapy against the incurable human poly(Q) disorders.

Glipizide ameliorates human poly(Q) mediated neurotoxicity by upregulating insulin signalling in Drosophila disease models.

Increasing reports suggest insulin signalling pathway as a putative drug target against polyglutamine [poly(Q)] disorders, such as Huntington's disease (HD), Spinocerebellar ataxias (SCA) 1, 2, 3 etc. However, studies on drug-based stimulation of insulin signalling cascade to mitigate poly(Q) pathogenesis are lacking. In our study, we adopted an evidence-based approach to examine if some established insulin stimulating drug can be utilized to restrict poly(Q) aetiology in Drosophila disease models. For the first time, we report that glipizide, an FDA approved anti-diabetic drug upregulates insulin signalling in poly(Q) expressing tissues and restricts formation of inclusion bodies and neurodegeneration. Moreover, it reinstates the chromatin architecture by improving histone acetylation, which is otherwise abrogated due to poly(Q) toxicity. In view of the functional conservation of insulin signalling pathway in Drosophila and humans, our finding strongly suggests that glipizide can be repurposed as an effective treatment strategy against the neurodegenerative poly(Q) disorders. Also, with appropriate validation studies in mammalian disease models, glipizide could be subsequently considered for the clinical trials in human patients.

Complementary Resistive Switching Behavior in Tetraindolyl Derivative-Based Memory Devices.

Complementary resistive switching (CRS) devices are more advantageous compared to bipolar resistive switching (BRS) devices for memory applications as they can minimize the sneak path problem observed in the case of BRS having a crossbar array structure. Here, we report the CRS behavior of 1,4-bis(di(1H-indol-3-yl)methyl)benzene (Indole1) molecules. Our earlier study revealed that Au/Indole1/Indium tin oxide (ITO) devices showed BRS under ambient conditions. However, the present investigations revealed that when the device is exposed to 353 K or higher temperatures, dynamic evolution of the Au/Indole1/ITO device from BRS to CRS occurred with a very good memory window (∼103), data retention (5.1 × 103 s), stability (50 days), and device yield (∼ 60%). This work explores the application possibility of indole derivatives toward future ultradense resistive random access memory.

Downregulation of glob1 mitigates human tau mediated neurotoxicity by restricting heterochromatin loss and elevating the autophagic response in drosophila.

BACKGROUND: Human neuronal tauopathies are typically characterized by the accumulation of hyperphosphorylated tau in the forms of paired helical filaments and/or neurofibrillary tangles in the brain neurons. Tau-mediated heterochromatin loss and subsequent global transcriptional upsurge have been demonstrated as one of the key factors that promotes tau toxicity. We have reported earlier that expression of human tau-transgene in Drosophila induces the expression of glob1, and its restored level restricts tau etiology by regulating tau hyperphosphorylation and ROS generation via GSK-3ß/p-Akt and Nrf2-keap1-ARE pathways, respectively. In view of this noted capability of glob1 in regulation of oxidative stress, and involvement of ROS in chromatin remodeling; we investigate if downregulation of glob1 restores tau-mediated heterochromatin loss in order to alleviate neurotoxicity. METHODS AND RESULTS: The tauV337M transgene was expressed in Drosophila eye by utilizing GAL4/UAS system. Expression of glob1 was depleted in tauV337M expressing tissues by co-expressing an UAS-glob1RNAi transgene by GMR-Gal4 driver. Immunostaining and wstern blot analysis suggested that tissue-specific downregulation of glob1 restores the cellular level of CBP and minimizes tau-mediated heterochromatin loss. It also assists in mounting an improved protective autophagic response to alleviate the human tau-induced neurotoxicity in Drosophila tauopathy models. CONCLUSIONS: Our study unfolds a novel aspect of the multitasking globin protein in restricting the pathogenesis of neuronal tauopathies. Interestingly, due to notable similarities between Drosophila glob1 and human globin gene(s), our findings may be helpful in developing novel therapeutic approaches against tauopathies.

The past and present of Drosophila models of traumatic brain injury.

Traumatic brain injuries are highly recognized as one of the leading causes of mortality and morbidity worldwide. A chronic and debilitating condition by nature, TBI is reportedly affecting the socio-economic well-being of society due to the unavailability of effective prophylaxis. Moreover, TBI is responsible for a myriad of systemic complications such as neurological deficits, gastrointestinal dysfunction, visual impairment, and disturbed circadian rhythm, to name a few. With increasing incidences of TBI-associated disabilities, there is an urgent need for better diagnostics and therapeutic interventions. An array of animal models has been developed to recapitulate pathophysiological conditions of TBI and to elucidate the course of cellular and molecular changes. Although mammalian models are pathophysiologically closer to humans, they decelerate the TBI research due to technical limitations. Therefore, various strategies have been established to model TBI in Drosophila that offer several advantages to study various attributes of TBI and provide a great opportunity for large-scale screening of potential drug molecules. In the present review, we have briefly summarized the fundamentals of brain injuries; contemporary advancements, contributions, and scope of Drosophila in TBI research.

Downregulation of glob1 suppresses pathogenesis of human neuronal tauopathies in Drosophila by regulating tau phosphorylation and ROS generation.

Human tauopathies represent a group of neurodegenerative disorders, characterized by abnormal hyperphosphorylation and aggregation of tau protein, which ultimately cause neurodegeneration. The aberrant tau hyperphosphorylation is mostly attributed to the kinases/phosphatases imbalance, which is majorly contributed by the generation of reactive oxygen species (ROS). Globin(s) represent a well-conserved group of proteins which are involved in O2 management, regulation of cellular ROS in different cell types. Similarly, Drosophila globin1 (a homologue of human globin) with its known roles in oxygen management and development of nervous system exhibits striking similarities with the mammalian neuroglobin. Several recent evidences support the hypothesis that neuroglobins are associated with Alzheimer's disease pathogenesis. We herein noted that targeted expression of human-tau induces the cellular level of Glob1 protein in Drosophila tauopathy models. Subsequently, RNAi mediated restored level of Glob1 restricts the pathogenic effect of human-tau by minimizing its hyperphosphorylation via GSK-3ß/p-Akt and p-JNK pathways. In addition, it also activates the Nrf2-keap1-ARE cascade to stabilize the tau-mediated increased level of ROS. These two parallel cellular events provide a significant rescue against human tau-mediated neurotoxicity in the fly models. For the first time we report a direct involvement of an oxygen sensing globin gene in tau etiology. In view of the fact that human genome encodes for the multiple Globin proteins including a nervous system specific neuroglobin; and therefore, our findings may pave the way to investigate if the conserved oxygen sensing globin gene(s) can be exploited in devising novel therapeutic strategies against tauopathies.

Resistive Switching of the Tetraindolyl Derivative in Ultrathin Films: A Potential Candidate for Nonvolatile Memory Applications.

Bipolar resistive switching using organic molecule is very promising for memory applications owing to their advantages, such as simple device structure, low manufacturing cost, stability, and flexibility. Herein we report Langmuir-Blodgett (LB) and spin-coated-film-based bipolar resistive switching devices using organic material 1,4-bis(di(1H-indol-3-yl)methyl)benzene (Indole1). The pressure-area per molecule isotherm (π-A), Brewster angle microscopy (BAM), atomic force microscopy (AFM), and scanning electron microscopy (SEM) were used to formulate an idea about the organization and morphology of the organic material onto thin films. On the basis of the device structure and measurement protocol, it is observed that the device made up of Indole1 shows nonvolatile resistive random access memory (RRAM) behavior with a very high memory window (∼106), data sustainability (5400 s), device yield (86.7%), and repeatability. The oxidation-reduction process and electric-field-driven conduction are the keys behind such switching behavior. Because of very good data retention, repeatability, stability, and a high device yield, the switching device designed using compound Indole1 may be a potential candidate for memory applications.

The S6k/4E-BP mediated growth promoting sub-pathway of insulin signalling cascade is essential to restrict pathogenesis of poly(Q) disorders in Drosophila.

Human neurodegenerative polyglutamine [poly(Q)] disorders, such as Huntington's disease (HD) and spinocerebellar ataxias (SCA), are characterised by an abnormal expansion of CAG repeats in the affected gene. The mutated proteins misfold and aggregate to form inclusion bodies that sequester important factors involved in cellular transcription, growth, stress and autophagic response and other essential functions. The insulin signalling pathway has been demonstrated as a major modifier and a potential drug target to ameliorate the poly(Q) mediated neurotoxicity in various model systems. Insulin signalling cascade harbours several downstream sub-pathways, which are synergistically involved in discharging indispensable biological functions such as growth and proliferation, metabolism, autophagy, regulation of cell death pathways etc. Hence, it is difficult to conclude whether the mitigation of poly(Q) neurotoxicity is an accumulative outcome of the insulin cascade, or the result of a specific sub-pathway. For the first time, we report that the ligand binding domain of insulin receptor mediated downstream growth promoting sub-pathway plays the pivotal role in operating the rescue event. We show that the growth promoting activity of insulin cascade is essential to minimize the abundance of inclusion bodies, to restrict neurodegeneration, and to restore the cellular transcriptional balance. Subsequently, we noted the involvement of the mTOR/S6k/4E-BP candidates in mitigating poly(Q) mediated neurotoxicity. Due to the conserved cellular functioning of the insulin cascade across species, and availability of several growth promoting molecules, our results in Drosophila poly(Q) models indicate towards a possibility of designing novel therapeutic strategies to restrict the pathogenesis of devastating human poly(Q) disorders.

Shaggy functions downstream of dMyc and their concurrent downregulation confers additive rescue against tau toxicity in Drosophila.

Neurodegenerative tauopathies such as Alzheimer's and Parkinson's diseases are characterized by hyperphosphorylation of tau protein and their subsequent aggregation in the forms of paired helical filaments and/or neurofibrillary tangles in specific areas of the brain. Despite several attempts, it remains a challenge to develop reliable biomarkers or effective drugs against tauopathies. It is increasingly evident now that due to the involvement of multiple cellular cascades affected by the pathogenic tau molecules, a single genetic modifier or a molecule is unlikely to be efficient enough to provide an inclusive rescue. Hence, multitargets based combinatorial approach(s) have been suggested to provide an efficient rescue against tauopathies. We have reported earlier that targeted downregulation of dmyc (a Drosophila homolog of human cmyc proto-oncogene) restricts tau etiology by limiting tau hyperphosphorylation and heterochromatin loss. Although, dmyc generates a significant rescue; however, it is not proficient enough to provide a complete alleviation against tauopathies. Here, we report that tissue-specific concurrent downregulation of dmyc and gsk3ß conveys a near-complete rescue against tau toxicity in Drosophila. We noted that combinatorial downregulation of dmyc and gsk3ß reduces tau hyperphosphorylation, restricts the formation of neurofibrillary tangles, and restores heterochromatin loss to the physiological level. Our subsequent investigations revealed that dmyc regulates gsk3ß via protein phosphatase 2A (dPP2A) in a dose-dependent manner to regulate tau pathogenesis. We propose that dmyc and gsk3ß candidates can be utilized in a synergistic manner for the development of an efficient combinatorial therapeutic approach against the devastating human tauopathies.

Age dependent trans-cellular propagation of human tau aggregates in Drosophila disease models.

Tauopathies is a class of neurodegenerative disorders which involves the transformation of physiological tau into pathogenic tau. One of the prime causes reported to drive this conversion is tau hyperphosphorylation and the subsequent propagation of pathogenic protein aggregates across the nervous system. Although past attempts have been made to deduce the details of tau propagation, yet not much is known about its mechanism. A better understanding of this aspect of disease pathology can prove to be beneficial for the development of diagnostic and therapeutic approaches. For the first time, we demonstrate that the human tau possesses an intrinsic property to spread trans-cellularly in the fly nervous system irrespective of the tau allele or the neuronal tissue type. Aggregate migration restricted by targeted down-regulation of a specific kinase, elucidates the role of hyper-phosphorylation in its movement. On the contrary to the previous models, our study delivers an easy and rapid in-vivo model for comprehensive examination of tau migration pathology. Henceforth, the developed model would not only be immensely helpful in uncovering the mechanistic in-depths of tau propagation pathology but also aid in modifier and/or drug screening for amelioration of tauopathies.

Dynamics of impurity in the environment of Dirac fermions.

We study the dynamics of a nonmagnetic impurity interacting with the surface states of a 3D and 2D topological insulator (TI). Employing the linked cluster technique we develop a formalism for obtaining the Green's function of the mobile impurity interacting with the low-energy Dirac fermions. We show that for the non-recoil case in 2D, the Green's function in the long-time limit has a power-law decay in time implying the breakdown of the quasiparticle description of the impurity. The spectral function in turn exhibits a weak power-law singularity. In the recoil case, however, the reduced phase-space for scattering processes implies a non-zero quasiparticle weight and the presence of a coherent part in the spectral function. Performing a weak coupling analysis we find that the mobility of the impurity reveals a T -3/2 divergence at low temperatures. In addition, we show that the Green's function of an impurity interacting with the helical edge modes (surface states of 2D TI) exhibit power-law decay in the long-time limit for both the non-recoil and recoil case (with low impurity momentum), indicating the break down of the quasiparticle picture. However, for impurity with high momentum, the quasiparticle picture is restored. The mobility of the heavy impurity interacting with the helical edge modes exhibits unusual behaviour. It has an exponential divergence at low temperatures which can be tuned to a power-law divergence, T -4, by the application of the magnetic field.

Reduced expression of dMyc mitigates TauV337M mediated neurotoxicity by preventing the Tau hyperphosphorylation and inducing autophagy in Drosophila.

Tauopathies such as Alzheimer's disease (AD), Pick's disease (PiD), Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) etc. represent a group of age-related neurodegenerative disorders in which tau protein loses its normal conformation mostly due to hyperphosphorylation and subsequent formation of the aggregates of defined shapes, known as Neurofibrillary Tangles (NFTs). We have demonstrated earlier that reduced dosage of dmyc (Drosophila homolog of human cmyc proto-oncogene) restricts tauWT mediated disease pathogenesis by regulating the phosphorylation status of tau. We demonstrate further that the downregulation of dmyc also alleviates the mutant human-tau (tauV337M) mediated neurotoxicity in Drosophila by improving disease defects. Moreover, tissue-specific downregulation of dmyc also induces cellular autophagy which facilitates the disposal of misfolded proteins via lysosome-mediated proteostasis. Our findings demonstrate the capability of dmyc in the suppression of different forms of human tauopathies in Drosophila disease models. Interestingly, due to the conserved characteristics of dmyc/cmyc across the animal kingdom, our study strengthens the possibility of utilizing this gene as an effective drug target against tauopathies.

Adequate expression of Globin1 is required for development and maintenance of nervous system in Drosophila.

Neurogenesis is driven by spatially and temporally regulated proliferation of neuronal progenitor cells that generates enormous number of assorted neurons to drive the complex behavior of an organism. Drosophila nervous system provides an advantageous model for identification and elucidation of the functional significance of the novel gene(s) involved in neurogenesis. The present study attempts to investigate the role(s) of globin1 (glob1) in the development and maintenance of the nervous system in Drosophila. It is increasingly clear now that globin genes play important role(s) in the various biological phenomena. The vertebrate neuroglobin has been reported to profoundly express in neuronal tissues and provides neuroprotection. We noted ubiquitous presence of Glob1 in the developing neuronal tissues with enhanced concentration throughout the VNC which comprises of midline cell clusters, which subsequently forms numerous types of progenitor cells and finally differentiate into specific neurons of the nervous system. Ubiquitous or pan-neuronal downregulation of glob1 causes partial lethality and mis-positioning of various neural-progenitor cells present in the embryonic midline cell clusters. Subsequently, profound expression of Glob1 was noted in the outer proliferation center of larval brain and photoreceptor axons of optic stalk. The overall arrangement of photoreceptor axons and stereotype positioning of neuroblast cells present in the central region of the brain were severally affected due to reduced expression of glob1. In addition, such larvae and surviving adults develop significant neuro-muscular disabilities. For the first time, our study suggests a novel role of glob1 in development and maintenance of the nervous system adding a new dimension to the functional significance of the multi-tasking glob1 gene in Drosophila.

Tissue-Specific Upregulation of Drosophila Insulin Receptor (InR) Mitigates Poly(Q)-Mediated Neurotoxicity by Restoration of Cellular Transcription Machinery.

Polyglutamine [poly(Q)] disorders are a class of trinucleotide repeat expansion neurodegenerative disorders which are dominantly inherited and progressively acquired with age. This group of disorders entail the characteristic formation of protein aggregates leading to widespread loss of neurons in different regions of the brain. SCA3 and HD, the two most commonly occurring types of poly(Q) disorders were examined in the present study. With the aim of elucidating novel genetic modifiers of poly(Q) disorders, the Drosophila insulin receptor (InR) was identified as a potential suppressor of poly(Q)-induced neurotoxicity and degeneration. We demonstrate for the first time that targeted upregulation of InR could effectively mitigate poly(Q)-mediated neurodegeneration in fly models. A significant reduction in poly(Q)-mediated cellular stress and apoptosis was noted upon InR overexpression in poly(Q) background. We further reveal that targeted upregulation of InR causes a substantial reduction in poly(Q) aggregate formation with the residual inclusion bodies localised to the cytoplasm. We also demonstrate that InR achieves suppression of poly(Q) toxicity by replenishing the cellular pool of CREB binding protein and improving the histone acetylation status of the cell. This leads to restoration of the cellular transcriptional machinery which is otherwise severely compromised in poly(Q) disease conditions. Interestingly, there also appeared a possibility of autophagy-mediated rescue of poly(Q) phenotype due to upregulation of InR. Therefore, our study strongly suggests that modulation of the insulin signalling pathway could be an effective therapeutic intervention against poly(Q) disorders.

Neurofibrillary tangles mediated human neuronal tauopathies: insights from fly models.

Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal and glial fibrillar lesions known as neurofibrillary tangles (NFTs). Tau is a neuron specific microtubule binding protein which is required for the integrity and functioning of neuronal cells, and hyperphosphorylation of tau and its subsequent aggregation and paired helical filaments (PHFs) and NFTs has emerged as one of the major pathogenic mechanisms of tauopathies in human and mammalian model systems. Modeling of human tauopathies in Drosophila results in manifestation of associated phenotypes, and a recent study has demonstrated that similar to human and mammalian models, accumulation of insoluble tau aggregates in the form of typical neurotoxic NFTs triggers the pathogenesis of tauopathies in fly models. In view of the availability of remarkable genetic tools, Drosophila tau models could be extremely useful for in-depth analysis of the role of NFTs in neurodegeneration and tau aetiology, and also for the screening of novel gene(s) and molecule(s) which suppress the toxicity of tau aggregates.