Rangappa, Nagaraj

Chinnathambi S., Rangappa N., Chandrashekar M.

Qureshi T., Chandrashekar M., Ananthanarayana V., Kumarappan M., Rangappa N., Velmurugan G., Chinnathambi S.

Chinnathambi S., Velmurugan G., Ananthanaraya V., Chandrashekar M., Rangappa N.

Chinnathambi S., Rangappa N., Chandrashekar M.

Qureshi T., Chandrashekar M., Ananthanarayana V., Kumarappan M., Rangappa N., Velmurugan G., Chinnathambi S.

Cho K., Kim G.W.

This study delineated the intricate relation between cholesterol metabolism, protein degradation mechanisms, and the pathogenesis of Huntington's disease (HD). Through investigations using both animal models and cellular systems, we have observed significant alterations in cholesterol levels, particularly in the striatum, which is the primary lesion site in HD. Our findings indicate the dysregulation of cholesterol metabolism-related factors, such as LDLR and SREBP2, in HD, which may contribute to disease progression. Additionally, we uncovered disruptions in protein degradation pathways, including decreased neddylated proteins and dysregulated autophagy, which further exacerbated HD pathology. Moreover, our study highlighted the potential therapeutic implications of targeting these pathways. By restoring cholesterol levels and modulating protein degradation mechanisms, particularly through interventions, such as MLN4924, we observed potential improvements in cellular function, as indicated by the increased BDNF levels. These insights underscore the importance of simultaneously addressing cholesterol metabolism and protein degradation to alleviate HD pathology. Collectively, this study provides a basic understanding of the interplay between the decrease of SREBP2 and the dysfunctional protein degradation system derived from disrupted cholesterol metabolism in HD and HD cells.

Chinnathambi S., Velmurugan G., Suresh S., Adithyan A., Chandrashekar M.

Chinnathambi S., Adithyan A., Chandrashekar M.

Chinnathambi S., Adithyan A., Suresh S., Velmurugan G., Chandrashekar M., Sahu S., Mishra M.

Chinnathambi S., Adityan A., Chandrashekar M.

Xie S., Li F.

Ependymal cells are arranged along the inner surfaces of the ventricles and the central canal of the spinal cord, providing anatomical, physiological and immunological barriers that maintain cerebrospinal fluid (CSF) homeostasis. Based on this, studies have found that alterations in gene expression, cell junctions, cytokine secretion and metabolic disturbances can lead to dysfunction of ependymal cells, thereby participating in the onset and progression of central nervous system (CNS) infections. Additionally, ependymal cells can exhibit proliferative and regenerative potential as well as secretory functions during CNS injury, contributing to neuroprotection and post-injury recovery. Currently, studies on ependymal cell primarily focus on the basic investigations of their morphology, function and gene expression; however, there is a notable lack of clinical translational studies examining the molecular mechanisms by which ependymal cells are involved in disease onset and progression. This limits our understanding of ependymal cells in CNS infections and the development of therapeutic applications. Therefore, this review will discuss the molecular mechanism underlying the involvement of ependymal cells in CNS infections, and explore their potential for application in clinical treatment modalities. Ependymal cells play an important role in the maintenance of CSF homeostasis and CNS health by forming physical and immune barriers against pathogen invasion. PPRs signaling pathways, cilia and intercellular junctions, cytokine secretion or senescence of ependymal cells can lead to dysfunction, which in turn is involved in the onset and progression of CNS infection. We propose potential therapeutic applications including gene transfer and novel biomarkers. Studies of ependymal cells have provided new ideas for pathophysiology and treatment, but further research is needed to fully understand their role in CNS infection and evaluate therapeutic effect.

Chinnathambi S.

Wang X.X., Ji X., Lin J., Wong I.N., Lo H.H., Wang J., Qu L., Wong V.K., Chung S.K., Law B.Y.

G protein-coupled receptors (GPCRs), widely expressed in the human central nervous system (CNS), perform numerous physiological functions and play a significant role in the pathogenesis of diseases. Consequently, identifying key therapeutic GPCRs targets for CNS-related diseases is garnering immense interest in research labs and pharmaceutical companies. However, using GPCRs drugs for treating neurodegenerative diseases has limitations, including side effects and uncertain effective time frame. Recognizing the rich history of herbal treatments for neurological disorders like stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), modern pharmacological research is now focusing on the understanding of the efficacy of traditional Chinese medicinal herbs and compounds in modulating GPCRs and treatment of neurodegenerative conditions. This paper will offer a comprehensive, critical review of how certain natural products and compounds target GPCRs to treat neurological diseases. Conducting an in-depth study of herbal remedies and their efficacies against CNS-related disorders through GPCRs targeting will augment our strategies for treating neurological disorders. This will not only broaden our understanding of effective therapeutic methodologies but also identify the root causes of altered GPCRs signaling in the context of pathophysiological mechanisms in neurological diseases. Moreover, it would be informative for the creation of safer and more effective GPCR-mediated drugs, thereby establishing a foundation for future treatment of various neurological diseases.

Soeda Y., Yoshimura H., Bannai H., Koike R., Shiiba I., Takashima A.

Intracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer's disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

Chinnathambi S., Velmurugan G., Chandrashekar M.

Chinnathambi S.

Guzmán-Ruíz M.A., Guerrero Vargas N.N., Ramírez-Carreto R.J., González-Orozco J.C., Torres-Hernández B.A., Valle-Rodríguez M., Guevara-Guzmán R., Chavarría A.

Microglia are highly dynamic cells that have been mainly studied under pathological conditions. The present review discusses the possible implication of microglia as modulators of neuronal electrical responses in physiological conditions and hypothesizes how these cells might modulate hypothalamic circuits in health and during obesity. Microglial cells studied under physiological conditions are highly diverse, depending on the developmental stage and brain region. The evidence also suggests that neuronal electrical activity modulates microglial motility to control neuronal excitability. Additionally, we show that the expression of genes associated with neuron-microglia interaction is down-regulated in obese mice compared to control-fed mice, suggesting an alteration in the contact-dependent mechanisms that sustain hypothalamic arcuate-median eminence neuronal function. We also discuss the possible implication of microglial-derived signals for the excitability of hypothalamic neurons during homeostasis and obesity. This review emphasizes the importance of studying the physiological interplay between microglia and neurons to maintain proper neuronal circuit function. It aims to elucidate how disruptions in the normal activities of microglia can adversely affect neuronal health.

Chen L., Saito R., Noda-Narita S., Kassai H., Aiba A.

Mechanistic target of rapamycin (mTOR) plays an important role in brain development and synaptic plasticity. Dysregulation of the mTOR pathway is observed in various human central nervous system diseases, including tuberous sclerosis complex, autism spectrum disorder (ASD), and neurodegenerative diseases, including Parkinson’s disease and Huntington’s disease. Numerous studies focused on the effects of hyperactivation of mTOR on cortical excitatory neurons, while only a few studies focused on inhibitory neurons. Here we generated transgenic mice in which mTORC1 signaling is hyperactivated in inhibitory neurons in the striatum, while cortical neurons left unaffected. The hyperactivation of mTORC1 signaling increased GABAergic inhibitory neurons in the striatum. The transgenic mice exhibited the upregulation of dopamine receptor D1 and the downregulation of dopamine receptor D2 in medium spiny neurons in the ventral striatum. Finally, the transgenic mice demonstrated impaired motor learning and dysregulated olfactory preference behavior, though the basic function of olfaction was preserved. These findings reveal that the mTORC1 signaling pathway plays an essential role in the development and function of the striatal inhibitory neurons and suggest the critical involvement of the mTORC1 pathway in the locomotor abnormalities in neurodegenerative diseases and the sensory defects in ASD.

Scharf P., Sandri S., Rizzetto F., Xavier L.F., Grosso D., Correia-Silva R.D., Farsky P.S., Gil C.D., Farsky S.H.

IntroductionG-protein coupled receptors (GPCRs) expressed on neutrophils regulate their mobilization from the bone marrow into the blood, their half-live in the circulation, and their pro- and anti-inflammatory activities during inflammation. Chronic kidney disease (CKD) is associated with systemic inflammatory responses, and neutrophilia is a hallmark of CKD onset and progression. Nonetheless, the role of neutrophils in CKD is currently unclear.MethodsBlood and renal tissue were collected from non-dialysis CKD (grade 3 - 5) patients to evaluate GPCR neutrophil expressions and functions in CKD development.ResultsCKD patients presented a higher blood neutrophil-to-lymphocyte ratio (NLR), which was inversely correlated with the glomerular filtration rate (eGFR). A higher frequency of neutrophils expressing the senescent GPCR receptor (CXCR4) and activation markers (CD18+CD11b+CD62L+) was detected in CKD patients. Moreover, CKD neutrophils expressed higher amounts of GPCR formyl peptide receptors (FPR) 1 and 2, known as neutrophil pro- and anti-inflammatory receptors, respectively. Cytoskeletal organization, migration, and production of reactive oxygen species (ROS) by CKD neutrophils were impaired in response to the FPR1 agonist (fMLP), despite the higher expression of FPR1. In addition, CKD neutrophils presented enhanced intracellular, but reduced membrane expression of the protein Annexin A1 (AnxA1), and an impaired ability to secrete it into the extracellular compartment. Secreted and phosphorylated AnxA1 is a recognized ligand of FPR2, pivotal in anti-inflammatory and efferocytosis effects. CKD renal tissue presented a low number of neutrophils, which were AnxA1+.ConclusionTogether, these data highlight that CKD neutrophils overexpress GPCRs, which may contribute to an unbalanced aging process in the circulation, migration into inflamed tissues, and efferocytosis.