SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

Fukunaga, Kohji; Yabuki, Yasushi

doi:10.1007/978-981-10-8488-1_9

Cited by 3 publications

(4 citation statements)

References 63 publications

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“…Cholinergic neurotransmission plays a key role in neuronal plasticity and cell survival in the central nervous system. Two types of AChRs, muscarinic AChRs (mAChRs) and nicotinic AChRs (nAChRs) ( Figure 1 ), trigger intracellular signaling via G-protein activity and ion influx, respectively [ 24 ]. In human brain, ACh is absorbed by a special transport system that has different pharmacological properties from the known organic cation transporters [ 25 ].…”

Section: Physiological Function Of Cholinergic Systemmentioning

confidence: 99%

Role of Cholinergic Signaling in Alzheimer’s Disease

et al. 2022

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Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.

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Section: Physiological Function Of Cholinergic Systemmentioning

confidence: 99%

Role of Cholinergic Signaling in Alzheimer’s Disease

et al. 2022

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“…Two manually curated groups of molecules with known agonistic and antagonistic activities were used as input for the cluster. The first group consisted of α7 nAChR agonists SAK3 (45), Nicotine, Acetylcholine, TC-1698 (46), PNU-282987 (Linn, 2016), DMXB (47), and ABT-107 (48). The second group was composed of receptor α7 antagonists and included methyllycaconitine (49), mecamylamine (50), neostigmine (51), anisodamine (52) and bupropion (53).…”

Section: Resultsmentioning

confidence: 99%

“…Structural similarities between analogs were compared to a manually curated dataset of 7 agonists and 5 antagonists of α7 nAChR with reported neuroprotective activity (45–53,72). This method allowed us to increase the size of the available data, robustness and reproducibility.…”

Section: Methodsmentioning

confidence: 99%

Novel computational deep learning strategy for neuroprotection identification reveals unique set of nicotine analogs as potential therapeutic compounds against Parkinson’s disease

Rojas-Rodríguez

Morantes

Pinzón

et al. 2019

Preprint

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Dopaminergic replacement has been used for Parkinson’s Disease (PD) treatment with positive effects on motor symptomatology but with low effects over disease progression and prevention. Different epidemiological studies have shown that nicotine consumption decreases PD prevalence through the activation of neuroprotective mechanisms. Nicotine-induced neuroprotection has been associated with the overstimulation of intracellular signaling pathways (SP) such as Phosphatidyl Inositol 3-kinase/Protein kinase-B (PI3K/AKT) through nicotinic acetylcholine receptors (e.g α7 nAChRs) and the over-expression of the anti-apoptotic gene Bcl-2. Considering its harmful effects (toxicity and dependency), the search for nicotine analogs with decreased secondary effects, but similar neuroprotective activity, remains a promissory field of study. In this work, a computational strategy integrating structural bioinformatics, signaling pathway (SP) manual reconstruction, and deep learning was performed to predict the potential neuroprotective activity of a series of 8 novel nicotine analogs over the behavior of PI3K/AKT. We performed a protein-ligand analysis between nicotine analogs and α7 nAChRs receptor using geometrical conformers, physicochemical characterization of the analogs and developed a manually curated neuroprotective dataset to analyze their potential activity. Additionally, we developed a predictive machine-learning model for neuroprotection in PD through the integration of Markov Chain Monte-Carlo transition matrix for the SP with synthetic training datasets of the physicochemical properties and structural dataset. Our model was able to predict the potential neuroprotective activity of seven new nicotine analogs based on the binomial Bcl-2 response regulated by the activation of PI3K/AKT. We present a new computational strategy to predict the pharmacological neuroprotective potential of nicotine analogs based on SP architecture, using deep learning and structural data. Our theoretical strategy can be further applied to the study new treatments related with SP deregulation and may ultimately offer new opportunities for therapeutic interventions in neurodegenerative diseases.Author SummaryParkinson’s disease is one of the most prevalent neurodegenerative diseases across population over age 50. Affecting controlled movements and non-motor symptoms, treatments for Parkinson prevention are indispensable to reduce patient’s population in the future. Epidemiological data provide evidence that nicotine have a neuroprotective effect decreasing Parkinson prevalence. By interacting with nicotine receptors in neurons and modulating signaling pathways expressing anti-apoptotic genes nicotine arise as a putative neuroprotective therapy. Nevertheless, toxicity and dependency prevent the use of nicotine as a suitable drug. Nicotine analogs, structurally similar compounds emerge as an alternative for Parkinson preventive treatment. In this sense we developed a quantitative strategy to predict the potential neuroprotective activity of nicotine analogs. Our model is the first approach to predict neuroprotection in the context of Parkinson and signaling pathways using machine learning and computational chemistry.

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“…As such, the results of our study offer evidence that cellular pathways altered in XDP-MSNs can be restored by SAK3 to alleviate the neurodegeneration phenotype in XDP-MSNs. SAK3, a T-type calcium channel activator has previously been studied in the context of other neurodegenerative disorders and in a mouse model of Taf1 knockdown (31,33,34,(71)(72)(73). SAK3 has also been shown to rescue behavioral phenotypes in a rat model of Taf1 intellectual disability syndrome (33).…”

Section: Discussionmentioning

confidence: 99%

SAK3 confers neuroprotection in the neurodegeneration model of X-linked Dystonia-Parkinsonism

Aryal,

Chen,

Burbach

et al. 2024

Preprint

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Background X-linked Dystonia-Parkinsonism(XDP) is an adult-onset neurodegenerative disorder that results in the loss of striatal medium spiny neurons (MSNs). XDP is associated with disease-specific mutations in and around the TAF1 gene. This study highlights the utility of directly reprogrammed MSNs from fibroblasts of affected XDP individuals as a platform that captures cellular and epigenetic phenotypes associated with XDP-related neurodegeneration. In addition, the current study demonstrates the neuroprotective effect of SAK3 currently tested in other neurodegenerative diseases. Methods XDP fibroblasts from three independent patients as well as age- and sex-matched control fibroblasts were used to generate MSNs by direct neuronal reprogramming using miRNA-9/9*-124 and thetranscription factors CTIP2, DLX1-P2A-DLX2, and MYT1L. Neuronal death, DNA damage, and mitochondrial health assays were carried out to assess the neurodegenerative state of directly reprogrammed MSNs from XDP patients (XDP-MSNs). RNA sequencing and ATAC sequencing were performed to infer changes in the transcriptomic and chromatin landscapesof XDP-MSNs compared to those of control MSNs (Ctrl-MSNs). Results Our results show that XDP patient fibroblasts can be successfully reprogrammed into MSNs and XDP-MSNs display several degenerative phenotypes, including neuronal death, DNA damage, and mitochondrial dysfunction, compared to Ctrl-MSNs reprogrammed from age- and sex-matched control individuals’ fibroblasts. In addition, XDP-MSNs showed increased vulnerability to TNFα -toxicity compared to Ctrl-MSNs. To dissect the altered cellular state in XDP-MSNs, we conducted transcriptomic and chromatin accessibility analyses using RNA- and ATAC-seq. Our results indicate that pathways related to neuronal function, calcium signaling, and genes related to other neurodegenerative diseases are commonly altered in XDP-MSNs from multiple patients. Interestingly, we found that SAK3, a T-type calcium channel activator, that may have therapeutic values in other neurodegenerative disorders, protected XDP-MSNs from neuronal death. Notably, we found that SAK3-mediated alleviation of neurodegeneration in XDP-MSNs was accompanied by gene expression changes toward Ctrl-MSNs.

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SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

Cited by 3 publications

References 63 publications

Role of Cholinergic Signaling in Alzheimer’s Disease

Role of Cholinergic Signaling in Alzheimer’s Disease

Novel computational deep learning strategy for neuroprotection identification reveals unique set of nicotine analogs as potential therapeutic compounds against Parkinson’s disease

SAK3 confers neuroprotection in the neurodegeneration model of X-linked Dystonia-Parkinsonism

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