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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) (GSK3β 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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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-3β/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 tau V337M transgene was expressed in Drosophila eye by utilizing GAL4/UAS system. Expression of glob1 was depleted in tau V337M 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., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

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 O 2 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-3β/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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 gsk3β conveys a near-complete rescue against tau toxicity in Drosophila. We noted that combinatorial downregulation of dmyc and gsk3β reduces tau hyperphosphorylation, restricts the formation of neurofibrillary tangles, and restores heterochromatin loss to the physiological level. Our subsequent investigations revealed that dmyc regulates gsk3β via protein phosphatase 2A (dPP2A) in a dose-dependent manner to regulate tau pathogenesis. We propose that dmyc and gsk3β candidates can be utilized in a synergistic manner for the development of an efficient combinatorial therapeutic approach against the devastating human tauopathies., (© 2021 International Union of Biochemistry and Molecular Biology.)

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.

Formation of Neurofibrillary Tangles (NFTs) in neuronal tissues has been implicated as the hallmark of disease pathogenesis and tau mediated toxicity in human and mammalian models. However, previous studies had failed to correlate NFT formation with pathogenesis of human neuronal tauopathies in Drosophila disease models. Though, a recent report suggests formation of tau mediated NFTs like structures confined to dopaminergic neurons in Drosophila adult brain; by utilizing various approaches, we demonstrate distinct and recurrent formation of NFTs in Drosophila neuronal tissues upon expression of wild type or mutant isoforms of human tau protein, and this appears as the key mediator of the pathogenesis of human neuronal tauopathy in Drosophila. Further, we show that tissue specific downregulation of dMyc (Drosophila homolog of human c-myc proto-oncogene) alleviates h-tau mediated cellular and functional deficits by restricting the formation of NFTs in neuronal tissues. Therefore, our findings provide very critical and novel insights about pathogenesis of human neuronal tauopathies in Drosophila disease models., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Human tauopathies such as Alzheimer's Disease (AD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease etc., are a group of neurodegenerative diseases which are characterized by abnormal hyperphosphorylation of tau that leads to formation of neurofibrillary tangles. Recapitulating several features of human neurodegenerative disorders, the Drosophila tauopathy model displays compromised lifespan, locomotor function impairment, and brain vacuolization in adult brain which is progressive and age dependent. Here, we demonstrate that tissue-specific downregulation of the Drosophila homolog of human c-myc proto-oncogene (dMyc) suppresses tau-mediated morphological and functional deficits by reducing abnormal tau hyperphosphorylation and restoring the heterochromatin loss. Our studies show for the first time that the inherent chromatin remodeling ability of myc proto-oncogenes could be exploited to limit the pathogenesis of human neuronal tauopathies in the Drosophila disease model. Interestingly, recent reports on successful uses of some anti-cancer drugs against Alzheimer's and Parkinson's diseases in clinical trials and animal models strongly support our findings and proposed possibility.

• Downregulation of dmyc mitigates human-tauV337M mediated neurotoxicity in Drosophila. • Downregulation of dmyc prevents toxic hyperphosphorylation of tauV337M. • Downregulation of dmyc elicits autophagic response in the tau models of 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. [ABSTRACT FROM AUTHOR]