Target For Neurodegenerative Diseases Research Articles

New Insights into Molecular Mechanisms Underlying Neurodegenerative Disorders.

As a large and heterogeneous group of disorders, neurodegenerative diseases are characterized by the progressive loss of structure or function in neurons, finally leading to neuronal death. Neurodegenerative diseases cause serious threat to a patient's quality of life and the most common are Alzheimer's disease and Parkinson's disease. Currently, little is known of the detailed etiology of these disorders; as such, there are no effective treatments available. Furthermore, the lack of targeted, effective, and resolvable therapy for neurodegenerative diseases, represents an expanding research field for the discovery of new therapeutic strategies. Investigations of the potential pathogenesis of neurodegenerative diseases will become the basis of preventing the occurrence and development of neurodegenerative diseases and finding effective therapies. Existing theories and mechanisms, such as genetic and environmental factors, abnormal protein accumulation, and oxidative stress, are intricately associated with each other. However, there is no molecular theory that can entirely explain the pathological processes underlying neurodegenerative diseases. Due to the development of experimental technology and the support of multidisciplinary integration, it has been possible to perform more in-depth research on potential targets for neurodegenerative diseases and there have been many exciting discoveries in terms of original theories and underlying mechanisms. With this review, we intend to review the existing literature and provide new insights into the molecular mechanisms underlying neurodegenerative diseases.

Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

BackgroundNeurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. MethodsWe screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. ResultsOur analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer’s disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson’s disease. Among them, GPNMB was the most promising target for Parkinson’s disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. ConclusionsOur study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.

Development of a Potent Nurr1 Agonist Tool for In Vivo Applications.

Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Despite strong evidence for a role in Parkinson's and Alzheimer's disease, pharmacological control and validation of Nurr1 are hindered by a lack of suitable ligands. We have discovered considerable Nurr1 activation by the clinically studied dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus calcium and systematically optimized this scaffold to a Nurr1 agonist with nanomolar potency, strong activation efficacy, and pronounced preference over the highly related receptors Nur77 and NOR1. The optimized compound induced Nurr1-regulated gene expression in astrocytes and exhibited favorable pharmacokinetics in rats, thus emerging as a superior chemical tool to study Nurr1 activation in vitro and in vivo.

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review.

Many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins and abnormal localization of organelles. These pathological features may be related to axonal transport deficits in neurons, which lead to failures in pathological protein targeting to specific sites for degradation and organelle transportation to designated areas needed for normal physiological functioning. Axonal transport deficits are most likely early pathological events in such diseases and gradually lead to the loss of axonal integrity and other degenerative changes. In this review, we investigated reports of mechanisms underlying the development of axonal transport deficits in a variety of common neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease to provide new ideas for therapeutic targets that may be used early in the disease process. The mechanisms can be summarized as follows: (1) motor protein changes including expression levels and post-translational modification alteration; (2) changes in microtubules including reducing stability and disrupting tracks; (3) changes in cargoes including diminished binding to motor proteins. Future studies should determine which axonal transport defects are disease-specific and whether they are suitable therapeutic targets in neurodegenerative diseases.

The KEAP1-NRF2 System and Neurodegenerative Diseases.

Significance: Central nervous system (CNS) diseases are disorders of the brain and/or spinal cord and include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor belonging to the cap-n-collar family that harbors a unique basic leucine zipper motif and plays as a master regulator of homeostatic responses. Recent Advances: Kelch-like ECH-associated protein 1 (KEAP1) is an adaptor of the Cullin3 (CUL3)-based ubiquitin E3 ligase that enhances the ubiquitylation of NRF2, which promotes the degradation of NRF2 to suppress its transcriptional activity in the absence of stress. Cysteine residues of KEAP1 are modified under stress conditions, and NRF2 degradation is attenuated, allowing it to accumulate and induce the expression of target genes. This regulatory system is referred to as the KEAP1-NRF2 system and plays a central role in protecting cells against various stresses. NRF2 also negatively regulates the expression of inflammatory cytokine and chemokine genes and suppresses pathological inflammation. As oxidative stress, inflammation, and proteostasis are known to contribute to neurodegenerative diseases, the KEAP1-NRF2 system is an attractive target for the treatment of these diseases. Critical Issues: In mouse models of neurodegenerative diseases, Nrf2 depletion exacerbates symptoms and enhances oxidative damage and inflammation in the CNS. In contrast, chemical or genetic NRF2 activation improves these symptoms. Indeed, the NRF2-activating chemical dimethyl fumarate is now widely used for the clinical treatment of MS. Future Directions: The KEAP1-NRF2 system is a promising therapeutic target for neurodegenerative diseases.

Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.

A summary of the current diagnostic methods for, and exploration of the value of microRNAs as biomarkers in, sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is an acute neurological deficit caused by severe sepsis without signs of direct brain infection, characterized by the systemic inflammation and disturbance of the blood-brain barrier. SAE is associated with a poor prognosis and high mortality in patients with sepsis. Survivors may exhibit long-term or permanent sequelae, including behavioral changes, cognitive impairment, and decreased quality of life. Early detection of SAE can help ameliorate long-term sequelae and reduce mortality. Half of the patients with sepsis suffer from SAE in the intensive care unit, but its physiopathological mechanism remains unknown. Therefore, the diagnosis of SAE remains a challenge. The current clinical diagnosis of SAE is a diagnosis of exclusion; this makes the process complex and time-consuming and delays early intervention by clinicians. Furthermore, the scoring scales and laboratory indicators involved have many problems, including insufficient specificity or sensitivity. Thus, a new biomarker with excellent sensitivity and specificity is urgently needed to guide the diagnosis of SAE. MicroRNAs have attracted attention as putative diagnostic and therapeutic targets for neurodegenerative diseases. They exist in various body fluids and are highly stable. Based on the outstanding performance of microRNAs as biomarkers for other neurodegenerative diseases, it is reasonable to infer that microRNAs will be excellent biomarkers for SAE. This review explores the current diagnostic methods for sepsis-associated encephalopathy (SAE). We also explore the role that microRNAs could play in SAE diagnosis and if they can be used to make the SAE diagnosis faster and more specific. We believe that our review makes a significant contribution to the literature because it summarizes some of the important diagnostic methods for SAE, highlighting their advantages and disadvantages in clinical use, and could benefit the field as it highlights the potential of miRNAs as SAE diagnostic markers.

CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death

Accumulation of aggregated and misfolded proteins, leading to endoplasmic reticulum stress and activation of the unfolded protein response, is a hallmark of several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Genetic screens are powerful tools that are proving invaluable in identifying novel modulators of disease associated processes. Here, we performed a loss-of-function genetic screen using a human druggable genome library, followed by an arrayed-screen validation, in human iPSC-derived cortical neurons. We identified and genetically validated 13 genes, whose knockout was neuroprotective against Tunicamycin, a glycoprotein synthesis inhibitor widely used to induce endoplasmic reticulum stress. We also demonstrated that pharmacological inhibition of KAT2B, a lysine acetyltransferase identified by our genetic screens, by L-Moses, attenuates Tunicamycin-mediated neuronal cell death and activation of CHOP, a key pro-apoptotic member of the unfolded protein response in both cortical and dopaminergic neurons. Follow-up transcriptional analysis suggested that L-Moses provided neuroprotection by partly reversing the transcriptional changes caused by Tunicamycin. Finally, L-Moses treatment attenuated total protein levels affected by Tunicamycin, without affecting their acetylation profile. In summary, using an unbiased approach, we identified KAT2B and its inhibitor, L-Moses, as potential therapeutic targets for neurodegenerative diseases.

Natural products regulate mitochondrial function in cognitive dysfunction-A scoping review.

Medicines from natural products can not only treat neurodegenerative diseases but also improve the cognitive dysfunction caused by treatments with western medicines. This study reviews the literature related to the regulation of mitochondrial participation in cognitive function by natural products. In this study, we focused on English articles in PubMed, Web of Science, and Google Scholar, from 15 October 2017, to 15 October 2022. Fourteen studies that followed the inclusion criteria were integrated, analyzed, and summarized. Several studies have shown that natural products can improve or reduce cognitive dysfunction by ameliorating mitochondrial dysfunction. These results suggest that natural products may serve as new therapeutic targets for neurodegenerative diseases.

The KEAP1-NRF2 system and neurodegenerative diseases.

Significance: Central nervous system (CNS) diseases are disorders of the brain and/or spinal cord and include neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). NF-E2-related factor 2 (NRF2) is a transcription factor belonging to the cap-n-collar (CNC) family that harbors a unique basic leucine zipper motif and plays as a master regulator of homeostatic responses. Recent Advances: Kelch-like ECH-associated protein 1 (KEAP1) is an adaptor of the Cullin3 (CUL3)-based ubiquitin E3 ligase that enhances the ubiquitylation of NRF2, which promotes the degradation of NRF2 to suppress its transcriptional activity in the absence of stress. Cysteine residues of KEAP1 are modified under stress conditions, and NRF2 degradation is attenuated, allowing it to accumulate and induce the expression of target genes. This regulatory system is referred to as the KEAP1-NRF2 system and plays a central role in protecting cells against various stresses. NRF2 also negatively regulates the expression of inflammatory cytokine and chemokine genes and suppresses pathological inflammation. As oxidative stress, inflammation, and proteostasis are known to contribute to neurodegenerative diseases, the KEAP1-NRF2 system is an attractive target for the treatment of these diseases. Critical Issues: In mouse models of neurodegenerative diseases, Nrf2 depletion exacerbates symptoms and enhances oxidative damage and inflammation in the CNS. In contrast, chemical or genetic NRF2 activation improves these symptoms. Indeed, the NRF2-activating chemical dimethyl fumarate (DMF) is now widely used for the clinical treatment of MS. Future Directions: The KEAP1-NRF2 system is a promising therapeutic target for neurodegenerative diseases.

The case for complement component 5 as a target in neurodegenerative disease

Introduction Complement-based drug discovery is undergoing a renaissance, empowered by new advances in structural biology, complement biology and drug development. Certain components of the complement pathway, particularly C1q and C3, have been extensively studied in the context of neurodegenerative disease, and established as key therapeutic targets. C5 also has huge therapeutic potential in this arena, with its druggability clearly demonstrated by the success of C5-inhibitor eculizumab. Areas covered We will discuss the evidence supporting C5 as a target in neurodegenerative disease, along with the current progress in developing different classes of C5 inhibitors and the gaps in knowledge that will help progress in the field. Expert opinion Validation of C5 as a therapeutic target for neurodegenerative disease would represent a major step forward for complement therapeutics research and has the potential to furnish disease-modifying drugs for millions of patients suffering worldwide. Key hurdles that need to be overcome for this to be achieved are understanding how C5a and C5b should be targeted to bring therapeutic benefit and demonstrating the ability to target C5 without creating vulnerability to infection in patients. This requires greater biological elucidation of its precise role in disease pathogenesis, supported by better chemical/biological tools.

GABAergic, GDNF and Sphingolipid Pathways Are Potentially Druggable Targets in Neurodegenerative Diseases: Lumping Is Better than Splitting.

GABAergic, GDNF and Sphingolipid Pathways Are Potentially Druggable Targets in Neurodegenerative Diseases: Lumping Is Better than Splitting.

Targeting Mitochondrial Sirtuins in Age-Related Neurodegenerative Diseases and Fibrosis.

Aging is a natural and complex biological process that is associated with widespread functional declines in numerous physiological processes, terminally affecting multiple organs and tissues. Fibrosis and neurodegenerative diseases (NDs) often occur with aging, imposing large burdens on public health worldwide, and there are currently no effective treatment strategies for these diseases. Mitochondrial sirtuins (SIRT3-5), which are members of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyltransferases, are capable of regulating mitochondrial function by modifying mitochondrial proteins that participate in the regulation of cell survival under various physiological and pathological conditions. A growing body of evidence has revealed that SIRT3-5 exert protective effects against fibrosis in multiple organs and tissues, including the heart, liver, and kidney. SIRT3-5 are also involved in multiple age-related NDs, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Furthermore, SIRT3-5 have been noted as promising targets for antifibrotic therapies and the treatment of NDs. This review systematically highlights recent advances in knowledge regarding the role of SIRT3-5 in fibrosis and NDs and discusses SIRT3-5 as therapeutic targets for NDs and fibrosis.

Protein – protein Interaction Mapping of Neurodegenerative Disease

Significant health risks are associated with neurodegenerative disorders. A variety of age-related factors have developed recently with the increase in the older population. These illnesses are characterised by the accumulation of proteins with altered physicochemical properties and the progressive degradation of neurons in the peritoneal and brain tissues. Some of the most challenging issues that modern nations face as their populations get older are Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The four types of proteins that are involved in these illnesses are Huntingtin, Alpha-synuclein, Amyloid beta, and TAR DNA-binding protein of 43 kDa (TDP-43). Dopamine release and transport may be regulated by alpha-synuclein. Tau, a microtubule-associated protein, binds to STXBP1, a critical component of the synaptic vesicle exocytotic machinery, reducing caspase-3 activation potential function in synaptic vesicle exocytosis, which reduces neuronal sensitivity to various apoptotic events. The String database was used to identify protein-protein interactions between targets for neurodegenerative diseases that overlapped and were therefore considered to be potential targets. These disorders are linked to four different gene types: APBA2, TARDBP, HTT, and SNCA. Twenty possible neurodegenerative diseases were present in all.

An Updated Evolutionary and Structural Study of TBK1 Reveals Highly Conserved Motifs as Potential Pharmacological Targets in Neurodegenerative Diseases.

TANK-binding kinase 1 protein (TBK1) is a kinase that belongs to the IκB (IKK) family. TBK1, also known as T2K, FTDALS4, NAK, IIAE8, and NF-κB, is responsible for the phosphorylation of the amino acid residues, serine and threonine. This enzyme is involved in various key biological processes, including interferon activation and production, homeostasis, cell growth, autophagy, insulin production, and the regulation of TNF-α, IFN-β, and IL-6. Mutations in the TBK1 gene alter the protein's normal function and may lead to an array of pathological conditions, including disorders of the central nervous system. The present study sought to elucidate the role of the TBK1 protein in amyotrophic lateral sclerosis (ALS), a human neurodegenerative disorder. A broad evolutionary and phylogenetic analysis of TBK1 was performed across numerous organisms to distinguish conserved regions important for the protein's function. Subsequently, mutations and SNPs were explored, and their potential effect on the enzyme's function was investigated. These analytical steps, in combination with the study of the secondary, tertiary, and quaternary structure of TBK1, enabled the identification of conserved motifs, which can function as novel pharmacological targets and inform therapeutic strategies for amyotrophic lateral sclerosis.

Central nervous system immunity in relation to aging and AD

The present report discusses the immune and clearance system of the central nervous system (CNS) in terms of its anatomical, physiological, and biochemical properties. There is now a growing body of evidence that progressive dysfunction of the meningeal lymphatic system should be considered as a risk factor for aging-related brain disorders. In addition, the activity of meningeal lymphatics may alter the access of CSF-carried immune neuromodulators to brain parenchyma, which is also involved in the onset of aging and AD. In the CNS clearance system, impairment of the BBB and small arteries, as well as the major protein of the end feet of astrocytes, AQP4, are associated with aging or AD. The idea of maximizing brain "waste discharge" as a new preventive or therapeutic target for neurodegenerative diseases in the context of healthy aging has been accepted.

Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes.

Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes.

Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics

Recent genome-wide association studies suggested shared genetic components between neurodegenerative diseases. However, pleiotropic association patterns among them remain poorly understood. We here analyzed 4 major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and found suggestively positive genetic correlation. We next implemented a gene-centric pleiotropy analysis with a powerful method called PLACO and detected 280 pleiotropic associations (226 unique genes) with these diseases. Functional analyses demonstrated that these genes were enriched in the pancreas, liver, heart, blood, brain, and muscle tissues; and that 42 pleiotropic genes exhibited drug-gene interactions with 341 drugs. Using Mendelian randomization, we discovered that AD and PD can increase the risk of developing ALS, and that AD and ALS can also increase the risk of developing FTD, respectively. Overall, this study provides in-depth insights into shared genetic components and causal relationship among the 4 major neurodegenerative diseases, indicating genetic overlap and causality commonly drive their co-occurrence. It also has important implications on the etiology understanding, drug development and therapeutic targets for neurodegenerative diseases.

Meccanismi comuni tra diabete e declino cognitivo

The increased prevalence of diabetes (DM) constitutes a major public health problem, primarily due to its numerous comorbidity and complications. It is widely demonstrated that DM is a significant risk factor for the development of cognitive impairment. Metabolic diseases can influence cognitive functions through multiple interconnected mechanisms. Cerebral insulin resistance, oxidative stress, neuroinflammation, and neuroendocrine dysfunctions can further the development of neurodegeneration diseases. The identification of the molecular mechanisms involved represents the target for the founding of early potential markers and new therapeutic targets of neurodegenerative diseases.

TRPM8 as a potential target in neurodegenerative diseases

AbstractBackgroundCholesterol is required by the neuronal cells for a normal brain functions as it affects membrane fluidity and ion channel functions by disrupting calcium homeostasis and neuronal loss1. Synthesis of cholesterol occurs in glial cells like astrocytes and get transported into neurons and intracellular organelles. Any deregulation in these transport leads to several neurodegenerative diseases2,3. TRPM8 cation channel has been found to contain conserved cholesterol binding motifs in its sequences that indicates its potential role in cholesterol mediated functions4.MethodConservation analysis of cholesterol binding motifs has been performed using CARC and CRAC sequences and docking of cholesterol with TRPM8 Cryo EM structure has been performed in Autodock. For in‐vitro studies, peripheral neurons were grown in cholesterol reduced condition. Co‐localization has been studied between TRPM8 and lipid‐raft marker by immunostaining.ResultTRPM8 has conserved cholesterol binding motifs in its structure. In‐vitro study shows that TRPM8 get localized on cholesterol enriched lipid‐raft on the plasma membrane more when cholesterol is reduced. The recruitment of TRPM8 protein also seems to increase in neuronal cell line after cholesterol reduction.ConclusionTRPM8 might have a cholesterol mediated role in neuronal cell dynamics which can be potential target for neurodegenerative diseases.