Papers by Debashis Mukhopadhyay
Biochemical and Biophysical Research Communications, 2012
APP intracellular C-terminal domain (AICD-47), generated upon γ-secretase cleavage of amyloid pre... more APP intracellular C-terminal domain (AICD-47), generated upon γ-secretase cleavage of amyloid precursor's protein (APP), bears the signature of a classical intrinsically unstructured domain (IUD). Comparing the recent crystal structures of AICD-47 peptides bound to its different adaptors such as protein-tyrosine-binding domain-2 (PTB2) of Fe65 and Src homology 2 (SH2) domain of growth factor receptor binding protein 2 (Grb2), the "conformational switching" of AICD-47 becomes evident. In order to understand different binding processes undertaken by this flexible molecule, upon recognizing different interfaces resulting in different 3D conformations, spectroscopic and calorimetric studies have been done. CD spectroscopy has revealed an overall random coil like structure in different pHs while TFE (2'-2'-2'-trifluoro ethanol) and HFIP (Hexa fluoro isopropanol) induced α-helicity to a certain extent. Binding of Tyr phosphorylated AICD-47 ((P)AICD-47) to Grb2-SH2 domain was carried out by a favorable enthalpic change (ΔH=-197.5±6.2 kcal mole(-1) at 25 °C) and an unfavorable entropic contribution (ΔS=-631 cal mol(-1) deg(-1) at 25 °C). Alternative conformation of AICD-47 in different biological contexts is another remarkable feature of IUDs which presumably has definitive roles in regulating Alzheimer's disease phenotype.
Pharmacogenetics, 2021
RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of ... more RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of insulin receptor family have emerged as a key common pathway across diseases. Thus we focussed on the Insulin receptor family and discussed the irregulation from the growth hormone axis. The signaling, regulation and physiology of the production in liver and CNS has never been discussed in signaling perspectives and is extremely crucial for understanding the possibilities of IGF1 in neurodegeneration specifically. The commonalities across neurodegenerative diseases such as oxidative stress, mitochondrial dysfunction, and protein misfolding and insulin pathway anomalies have been elucidated and correlated with the insulin pathway. The crosstalk possibilities of the pathways, along with other regulatory modes for the development of combinatorial therapy have been discussed to visualize a common platform for neurodegenerative diseases including AD, PD, HD, ALS and FTD. Furthermore, the incr...
This article cites 39 articles, 18 of which can be accessed free
Journal of Proteins & Proteomics, 2013
Brain senescence is as obvious as death. It is associated with structural as well as functional c... more Brain senescence is as obvious as death. It is associated with structural as well as functional compromises of the brain. Decline in cognitive function can also be associated with aging brain. Both genomics and proteomics study of the aging brain should help in deciphering the process of senescence. Results from this kind of "omics" studies, mainly proteomics, reveal that there is always a correlation of brain senescence with neurodegenerative diseases like Alzheimer's disease (AD), though successful aging without neurodegeneration is possible. Changes at the proteome level can reflect normal aging to mild cognitive impairment to a neurodegenerative disease like AD. Some additional factors are also identified which can enhance or reduce the senescence process. This article is a brief account of those and a mandate towards what could be done to understand the mechanism of brain aging and its correlation with neurodegeneration.
The dynamic field of neurosciences entails ever increasing search for molecular mechanisms of dis... more The dynamic field of neurosciences entails ever increasing search for molecular mechanisms of disease states, especially in the domain of neurodegenerative disorders. The previous century heralded the techniques in proteomics when indexing of the human proteomes relating to various disease conditions became important. Early stage research in certain diseases or pathological conditions requires a more holistic approach of first discovering the pro teins of interest for the condition. Despite its limitations, proteomics is one of the most powerful techniques available to us today to dissect the molecular scenario in a particular disease situation. In this review we will discuss about the current clinical research in neurodegenerative disorders that employ proteomics techniques. We will specifically focus on our understanding of Alzheimer’s disease, traumatic spinal cord injury and neuromyelitis optica. Discussions will include ongoing worldwide research in these areas, research in Ind...
Supplementary Movie legend. https://www.saha.ac. in/sg/www/movie.htm. The movie is showing fusion ... more Supplementary Movie legend. https://www.saha.ac. in/sg/www/movie.htm. The movie is showing fusion of Grb2-DsRed containing smaller vesicles leading to the formation of enlarged late endosome in Neuro 2A cells. After 3 h of transient transfections, individual frames were collected using confocal microscope at 7 min interval for first 3 snaps and then after each 3 min interval for one and half hour.
RSC Advances
Aggregation of intrinsically disordered as well as the ordered proteins under certain premises or... more Aggregation of intrinsically disordered as well as the ordered proteins under certain premises or physiological conditions leads to pathological disorder.
Journal of Neuroimmunology
Biochemical Journal
Alzheimer's Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resista... more Alzheimer's Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance. Reportedly, two non-canonical Receptor Tyrosine Kinases (RTKs), ALK and RYK, both targets of the same micro RNA miR-1271, exhibit significant and consistent functional down-regulation in post-mortem AD and T2D tissues. Incidentally, both have Grb2 as a common downstream adapter and NOX4 as a common ROS producing factor. Here we show that Grb2 and NOX4 play critical roles in reducing the severity of both the diseases. The study demonstrates that the abundance of Grb2 in degenerative conditions, in conjunction with NOX4, reverse cytoskeletal degradation by counterbalancing the network of small GTPases. PAX4, a transcription factor for both Grb2 and NOX4, emerges as the key link between the common pathways of AD and T2D. Down-regulation of both ALK and RYK through miR-1271, elevates the PAX4 level by reducing its suppressor ARX via Wnt/β-Catenin signaling. For the first time, this stud...
RSC Advances
Aggregation of intrinsically disordered as well as the ordered proteins under certain premises or... more Aggregation of intrinsically disordered as well as the ordered proteins under certain premises or physiological conditions leads to pathological disorder. Here we have presented a detailed investigation on the effect of a porous metallic (Au) and a non-metallic (Si) nanomaterial on the formation of ordered (fiber-like/amyloid) and disordered (amorphous) aggregates of proteins. Porous nanogold (PNG) was found to reduce the amyloid aggregation of insulin but does not have much impact on the lag phase in the aggregation kinetics, whereas porous nano-silica (PNS) was found both to decrease the amount of aggregation as well as prolong the lag phase of amyloid fiber formation from insulin. On the other hand, both the porous nanoparticles are found to decrease the extent of amorphous aggregation (with slight improvement for PNS) of pathogenic huntingtin (Htt) protein in Huntington's disease cell model. This is a noted direct observation in controlling and understanding protein aggregation diseases which may help us to formulate nanotherapeutic drugs for future clinical applications.
Journal of Proteins and Proteomics
Devic’s disease or neuromyelitis optica is an autoimmune inflammatory disease of the central nerv... more Devic’s disease or neuromyelitis optica is an autoimmune inflammatory disease of the central nervous system that primarily affects the brain and spinal cord. Autoantibodies target the primary water channel of the brain, aquaporin 4 (Aqp4), and thereby initiate a cascade of downstream events of inflammation, complement activation ultimately resulting in astrocyte death and loss of oligodendrocytes. Proteomic analysis of serum, cerebrospinal fluid as well as urine of NMO patients successfully identified unique protein signatures that get altered. Besides oral steroids and immunosuppressants, Rituximab (RTX) remains the preferred therapy for NMO patients. Our study focuses on the identification of the isoformic patterns of some of the major serum proteins and how the profiles shift in patients after receiving immunosuppressant therapy. Some of the significant modifications include major shifts in the spot pattern of abundant serum proteins like ApoA1, FGG, and HP towards the acidic side of the pH after treatment. This qualitative comparative analysis among NMO patients, before and after therapy, would be useful to provide insight into the associated disease dynamics.
Current Alzheimer Research
Neurodegenerative Diseases (NDD) are the major contributors to age-related causes of mental disab... more Neurodegenerative Diseases (NDD) are the major contributors to age-related causes of mental disability on a global scale. Most NDDs, like Alzheimer’s Disease (AD), are complex in nature - implying that they are multi-parametric both in terms of heterogeneous clinical outcomes and underlying molecular paradigms. Emerging evidence from high throughput genomic, transcriptomic and small RNA sequencing experiments hint at the roles of long non-coding RNAs (lncRNAs) in AD. X-inactive Specific Transcript (XIST), a component of the Xic, the X-chromosome inactivation centre, is an RNA gene on the X chromosome of the placental mammals indispensable for the X inactivation process. An extensive literature survey shows that aberrations in Xist expression and in some cases, a disruption of the Xchromosome inactivation as a whole play a significant role in AD. Considering the enormous potential of Xist as an endogenous silencing molecule, the idea of using Xist as a non-conventional chromosome sil...
Alzheimer’s Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance.... more Alzheimer’s Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance. Besides Insulin Receptor (IR), two non-canonical RTKs, ALK and RYK, exhibit significant and consistent functional downregulation in post-mortem AD and T2D tissues. Incidentally, both have Grb2 as a common downstream adapter and NOX4 as a common ROS producing factor. Here we show that Grb2 and NOX4 play critical roles in reducing the severity of both the diseases. The study demonstrates that the abundance of Grb2 in degenerative conditions, in conjunction with NOX4, reverse cytoskeletal degradation by counterbalancing the network of small GTPases. PAX4, a transcription factor for both Grb2 and NOX4, emerges as the key link between the common pathways of AD and T2D. Both ALK and RYK downregulation elevate the PAX4 level by reducing its suppressor ARX via Wnt/β-Catenin signaling pathway. For the first time, this study brings together RTKs other than Insulin Receptor (IR), their common tran...
Molecular and Cellular Biochemistry
Alzheimer’s disease (AD) and type 2 diabetes (T2D) share the common hallmark of insulin resistanc... more Alzheimer’s disease (AD) and type 2 diabetes (T2D) share the common hallmark of insulin resistance. It is conjectured that receptor tyrosine kinases (RTKs) play definitive roles in the process. To decipher the signaling overlap behind this phenotypic resemblance, the activity status of RTKs is probed in post-mortem AD and T2D tissues and cell models. Activities of only about one-third changed in a similar fashion, whereas about half of them showed opposite outcomes when exposed to contrasting signals akin to AD and T2D. Interestingly, irrespective of disease type, RTKs with enhanced and compromised activities clustered distinctly, indicating separate levels of regulations. Similar regulatory mechanisms within an activity cluster could be inferred, which have potential to impact future therapeutic developments.
The FEBS Journal
Mitofusin‐2 (MFN2) is primarily involved in mitochondrial fusion and participates in diverse biol... more Mitofusin‐2 (MFN2) is primarily involved in mitochondrial fusion and participates in diverse biological processes. Several reports show that MFN2 is a target of different miRNAs; however, the transcriptional regulation of MFN2 has not been extensively studied. To gain insight into the transcriptional regulation of MFN2, we expressed E2F transcription factor 1 (E2F1) exogenously and observed that it increased the endogenous expression of MFN2 by binding to its putative promoter region. Although the levels of E2F1 were shown to vary during the cell cycle, the expression of MFN2 and its regulator SP1 did not change throughout the different phases, suggesting that E2F1 regulates MFN2 in a cell‐cycle‐independent manner. In the cell‐cycle phases, where the expression of E2F1 was reduced, SP1 might act in its place to regulate the expression of MFN2. We showed that E2F1 and SP1 are present as a complex on the promoter of MFN2 during the S‐phase as well as in E2F1 overexpressing cells, suggesting that they may regulate the expression of MFN2 synergistically. Furthermore, we found that E2F1 modulated mitochondrial fusion and mitophagy, likely through regulation of MFN2. Bioinformatic analysis revealed that several potential targets of E2F1 are localized in mitochondria and associated with autophagy. Collectively, these data identify the E2F1–MFN2 axis as a regulator of mitochondrial morphology and mitophagy, suggesting a potential therapeutic target for the treatment of mitochondrial disorders.
Alzheimer's & Dementia: Translational Research & Clinical Interventions
Amyloid fibrils are misfolded, protease‐resistant forms of normal proteins. They are infectious s... more Amyloid fibrils are misfolded, protease‐resistant forms of normal proteins. They are infectious such as prions or noninfectious such as β‐amyloid (Aβ) fibrils causing Alzheimer's disease (AD). Prions and amyloids are structurally similar, possessing cross β‐pleated sheet‐like structures. As microbial keratinase could degrade prions, we tested keratinase activity on Aβ fibrils.
RNA Biology
Altered expression levels of protein-coding genes and microRNAs have been implicated in the patho... more Altered expression levels of protein-coding genes and microRNAs have been implicated in the pathogenesis of Huntington's disease (HD). The involvement of other ncRNAs, especially long ncRNAs (lncRNA), is being realized recently and the related knowledge is still rudimentary. Using small RNA sequencing and PCR arrays we observed perturbations in the levels of 12 ncRNAs in HD mouse brain, eight of which had human homologs. Of these, Meg3, Neat1, and Xist showed a consistent and significant increase in HD cell and animal models. Transient knock-down of Meg3 and Neat1 in cell models of HD led to a significant decrease of aggregates formed by mutant huntingtin and downregulation of the endogenous Tp53 expression. Understanding Meg3 and Neat1 functions in the context of HD pathogenesis is likely to open up new strategies to control the disease.
Uploads
Papers by Debashis Mukhopadhyay