Deacylases-structure, function, and relationship to diseases.

Reversible S-acylation plays a pivotal role in various biological processes, modulating protein functions such as subcellular localization, protein stability/activity, and protein-protein interactions. These modifications are mediated by acyltransferases and deacylases, among which the most abundant modification is S-palmitoylation. Growing evidence has shown that this rivalrous pair of modifications, occurring in a reversible cycle, is essential for various biological functions. Aberrations in this process have been associated with various diseases, including cancer, neurological disorders, and immune diseases. This underscores the importance of studying enzymes involved in acylation and deacylation to gain further insights into disease pathogenesis and provide novel strategies for disease treatment. In this Review, we summarize our current understanding of the structure and physiological function of deacylases, highlighting their pivotal roles in pathology. Our aim is to provide insights for further clinical applications.

Update on the Development of MNK Inhibitors as Therapeutic Agents.

Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2) represent a central class of enzymes that are activated by extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases. MNK1 and MNK2 coordinate cellular signaling, control production of inflammatory chemokines, and regulate cell proliferation and survival. MNK1/2 are referred to as serine/threonine kinases as they phosphorylate serine or threonine residues on their substrates. Upon activation, MNK1/2 phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at Ser209, which in turn initiates ribosome assembly and protein translation. Deleterious overexpression of MNK1/2 and/or eIF4E have been reported in several diseases including cancers, neurological disorders, autism, and inflammation. Recently, there have been intense efforts toward the development of potent and selective inhibitors of MNK1/2 in both academia and industry. Herein, we review the current understanding of the structural and biological aspects of MNK1/2 and provide an update of pharmacological inhibitors of MNK1/2 including candidates in clinical trials.

The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders.

The serine/threonine p21-activated kinases (PAKs), as main effectors of the Rho GTPases Cdc42 and Rac, represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity. PAKs show wide expression in the brain, but they differ in specific cell types, brain regions, and developmental stages. PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines. PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders. Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment, comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases, which may also represent potential therapeutic targets of these diseases.

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes.

OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237.

Risks and rewards of targeting NAD+ homeostasis in the brain.

Strategies to correct declining nicotinamide adenine dinucleotide (NAD+) levels in neurological disease and biological ageing are promising therapeutic candidates. These strategies include supplementing with NAD+ precursors, small molecule activation of NAD+ biosynthetic enzymes, and treatment with small molecule inhibitors of NAD+ consuming enzymes such as CD38, SARM1 or members of the PARP family. While these strategies have shown efficacy in animal models of neurological disease, each of these has the mechanistic potential for adverse events that could preclude their preclinical use. Here, we discuss the implications of these strategies for treating neurological diseases, including potential off-target effects that may be unique to the brain.

The angiotensin converting enzyme 2 (ACE2) system in the brain: possible involvement in Neuro-Covid.

The brain has its own intrinsic renin-angiotensin system (RAS) with all its components present in the central nervous system (CNS). Recent data demonstrate that also the main components of the angiotensin concerting enzyme 2 (ACE2) system (at least ACE2 itself, as well as the biologically active angiotensin (1-7) and its cognate receptor Mas) are expressed in the brain. Aside from these members, alamadine and MrgD are discussed as further members that have neuro-active roles in the CNS. Little is known about the possible functions of MrgD within the brain. Concerning angiotensin (1-7) acting through the Mas receptor, data were accumulating that this system is involved in numerous processes contributing to neuronal plasticity and even learning and memory. Malfunctions in the brain ACE2 system are associated with disturbances in neuronal plasticity. Since SARS-CoV-2 has a high affinity towards ACE2, Neuro-Covid may directly or indirectly depend on a disturbed balance in the ACE2 derived angiotensin system in the brain. Since the ACE2 system in the brain is far from being understood, a deeper understanding of e.g. the angiotensin (1-7) / Mas system is needed, especially with regard to the roles of angiotensin (1-7) in neuronal plasticity.

Physiological functions and therapeutic applications of neutral sphingomyelinase and acid sphingomyelinase.

Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.

A patent review of adaptor associated kinase 1 (AAK1) inhibitors (2013-present).

INTRODUCTION: Adaptor-associated kinase 1 (AAK1) has been proposed as being a promising drug target for the treatment of a variety of neurological and psychiatric disorders, such as schizophrenia, cognitive deficits in schizophrenia, Parkinson's disease, bipolar disorder, Alzheimer's disease and neuropathic pain. More recently, AAK1 was shown to be an essential cellular factor for viral replication and therefore has been pursued as a host target for the development of broad-spectrum antiviral agents. AREAS COVERED: This review provides an overview of the patented AAK1 inhibitors from 2013 to present. EXPERT OPINION: The promise of AAK1 as drug target for the treatment of neuropathic pain stimulated the search for AAK1 inhibitors. However, only two companies (i.e. Lexicon Pharmaceuticals and Bristol Myers Squibb) seemed to be active in this field and filed patent applications in the last few years. The most promising congeners showed promising in vitro activity in a variety of AAK1-related assays. Moreover, selected compounds were also endowed with in vivo activity in various preclinical animal models for neuropathic pain.

Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase.

Aminoacyl-RNA synthetases (aaRSs) are among the key enzymes of protein biosynthesis. They are responsible for conducting the first step in the protein biosynthesis, namely attaching amino acids to the corresponding tRNA molecules both in cytoplasm and mitochondria. More and more research demonstrates that mutations in the genes encoding aaRSs lead to the development of various neurodegenerative diseases, such as incurable Charcot-Marie-Tooth disease (CMT) and distal spinal muscular atrophy. Some mutations result in the loss of tRNA aminoacylation activity, while other mutants retain their classical enzyme activity. In the latter case, disease manifestations are associated with additional neuron-specific functions of aaRSs. At present, seven aaRSs (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, MetRS, and LysRS) are known to be involved in the CMT etiology with glycyl-tRNA synthetase (GlyRS) being the most studied of them.

The role of monoamine oxidase enzymes in the pathophysiology of neurological disorders.

Monoamine oxidase enzymes are responsible for the degredation of serotonin, dopamine, and norepinephrine in the central neurvous system. Although it has been nearly 100 years since they were first described, we are still learning about their role in the healthy brain and how they are altered in various disease states. The present review provides a survey of our current understanding of monoamine oxidases, with a focus on their contributions to neuropsychiatric, neurodevelopmental, and neurodegenerative disease. Important species differences in monoamine oxidase function and development in the brain are highlighted. Sex-specific monoamine oxidase regulatory mechanisms and their implications for various neurological disorders are also discussed. While our understanding of these critical enzymes has expanded over the last century, gaps exist in our understanding of sex and species differences and the roles monoamine oxidases may play in conditions often comorbid with neurological disorders.

Crosstalk among Calcium ATPases: PMCA, SERCA and SPCA in Mental Diseases.

Calcium in mammalian neurons is essential for developmental processes, neurotransmitter release, apoptosis, and signal transduction. Incorrectly processed Ca2+ signal is well-known to trigger a cascade of events leading to altered response to variety of stimuli and persistent accumulation of pathological changes at the molecular level. To counterbalance potentially detrimental consequences of Ca2+, neurons are equipped with sophisticated mechanisms that function to keep its concentration in a tightly regulated range. Calcium pumps belonging to the P-type family of ATPases: plasma membrane Ca2+-ATPase (PMCA), sarco/endoplasmic Ca2+-ATPase (SERCA) and secretory pathway Ca2+-ATPase (SPCA) are considered efficient line of defense against abnormal Ca2+ rises. However, their role is not limited only to Ca2+ transport, as they present tissue-specific functionality and unique sensitive to the regulation by the main calcium signal decoding protein-calmodulin (CaM). Based on the available literature, in this review we analyze the contribution of these three types of Ca2+-ATPases to neuropathology, with a special emphasis on mental diseases.

PARP overactivation in neurological disorders.

Poly (ADP-ribose) polymerases (PARPs) constitute a family of enzymes associated with divergent cellular processes that are not limited to DNA repair, chromatin organization, genome integrity, and apoptosis but also found to play a crucial role in inflammation. PARPs mediate poly (ADP-ribosylation) of DNA binding proteins that is often responsible for chromatin remodeling thereby ensure effective repairing of DNA stand breaks although during the conditions of severe genotoxic stress PARPs direct the cell fate towards apoptotic events. Recent discoveries have pushed PARPs into the spotlight as targets for treating cancer, metabolic, inflammatory and neurological disorders. Of note, PARP-1 is the most abundant isoform of PARPs (18 member super family) which executes more than 90% of PARPs functions. Since oxidative/nitrosative stress actuated PARP-1 is linked to vigorous DNA damage and wide spread provocative inflammatory response that underlie the aetiopathogenesis of different neurological disorders, possibility of developing PARP-1 inhibitors as plausible neurotherapeutic agents attracts considerable research interest. This review outlines the recent advances in PARP-1 biology and examines the capability of PARP-1 inhibitors as treatment modalities in intense and interminable diseases of neuronal origin.

Pathophysiological functions of Rnd proteins.

Rnd proteins constitute a subfamily of Rho GTPases represented in mammals by Rnd1, Rnd2 and Rnd3. Despite their GTPase structure, their specific feature is the inability to hydrolyse GTP-bound nucleotide. This aspect makes them atypical among Rho GTPases. Rnds are regulated for their expression at the transcriptional or post-transcriptional levels and they are activated through post-translational modifications and interactions with other proteins. Rnd proteins are mainly involved in the regulation of the actin cytoskeleton and cell proliferation. Whereas Rnd3 is ubiquitously expressed, Rnd1 and 2 are tissue-specific. Increasing data has described their important role during development and diseases. Herein, we describe their involvement in physiological and pathological conditions with a focus on the neuronal and vascular systems, and summarize their implications in tumorigenesis.

Chitinases and chitinase-like proteins as biomarkers in neurologic disorders.

Chitinases are hydrolytic enzymes widely distributed in nature. Despite their physiologic and pathophysiologic roles are not well understood, chitinases are emerging as biomarkers in a broad range of neurologic disorders, where in many cases, protein levels measured in the CSF have been shown to correlate with disease activity and progression. In this review, we will summarize the structural features of human chitinases and chitinase-like proteins and their potential physiologic and pathologic functions in the CNS. We will also review existing evidence for the role of chitinases and chitinase-like proteins as diagnostic and prognostic biomarkers in inflammatory, neurodegenerative diseases, and psychiatric disorders. Finally, we will comment on future perspectives of chitinase studies in neurologic conditions.

Emerging Roles of USP18: From Biology to Pathophysiology.

Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine-tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18. We also highlight new insights into how USP18 is implicated not only in physiology but also in pathogenesis of various human diseases, involving infectious diseases, neurological disorders, and cancers. Eventually, we integrate a discussion of the potential of therapeutic interventions for targeting USP18 for disease treatment.

Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders.

Phosphodiesterases (PDE) are a diverse family of enzymes (11 isoforms so far identified) responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases-chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders etc. In 2011, roflumilast, a PDE4 inhibitor (PDE4I) was approved for the treatment of COPD. Subsequently, other PDE4 inhibitors (PDE4Is) like apremilast and crisaborole were approved by the Food and Drug Administration (FDA) for psoriasis, atopic dermatitis etc. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop allosteric modulation with high specificity to PDE4 isoforms having better efficacy and lesser adverse effects. Interestingly, repositioning PDE4Is towards neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and sleep disorders, is gaining attention. This review is an attempt to summarize the data on the effects of PDE4 overexpression in neurological disorders and the use of PDE4Is and newer allosteric modulators as therapeutic options. We have also compiled a list of on-going clinical trials on PDE4 inhibitors in neurological disorders.

Slow-binding inhibitors of acetylcholinesterase of medical interest.

Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition: a) slow binding rate constant kon, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action. Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Redox signalling and regulation of the blood-brain barrier.

Neurological disorders are associated with increased oxidative stress. Reactive oxidants damage tissue and promote cell death, but it is apparent that oxidants can have more subtle effects on cell function through the modulation of redox-sensitive signalling pathways. Cells of the blood-brain barrier regulate the brain microenvironment but become dysfunctional during neurological disease. The blood-brain barrier is maintained by many cell types, and is modulated by redox-sensitive pathways, ranging from the cytoskeletal elements responsible for establishing a barrier, to growth factor and cytokine signalling pathways that influence neurovascular cells. During neurological disease, blood-brain barrier cells are exposed to exogenously generated oxidants from immune cells, as well as increasing endogenously oxidant production. These oxidants impair the function of the blood-brain barrier, leading to increased leakage and reduced blood flow. Reducing the impact of oxidants on the function of blood-brain barrier cells may provide new strategies for delaying the progression of neurological disease.

The biological role of arachidonic acid 12-lipoxygenase (ALOX12) in various human diseases.

ALOX12 encodes arachidonic acid 12-lipoxygenase that acts on different polyunsaturated fatty acid substrates to produce biologically active lipid mediators including eicosanes and lipoxins. ALOX12 protein plays an important role in inflammation and oxidation, while abnormal DNA methylation and genetic variants of ALOX12 are associated with various human diseases and pathological phenotypes, such as cardiovascular disease, diabetes, neurodegenerative diseases, respiratory system disease, cancer, infection, etc. Here, this article reviews the mechanisms by which ALOX12 participates in related diseases, which will provide systematic knowledge for future ALOX12 related studies.

Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions.

Fyn is a non-receptor or cytoplasmatic tyrosine kinase (TK) belonging to the Src family kinases (SFKs) involved in multiple transduction pathways in the central nervous system (CNS) including synaptic transmission, myelination, axon guidance, and oligodendrocyte formation. Almost one hundred years after the original description of Fyn, this protein continues to attract extreme interest because of its multiplicity of actions in the molecular signaling pathways underlying neurodevelopmental as well as neuropathologic events. This review highlights and summarizes the most relevant recent findings pertinent to the role that Fyn exerts in the brain, emphasizing aspects related to neurodevelopment and synaptic plasticity. Fyn is a common factor in healthy and diseased brains that targets different proteins and shapes different transduction signals according to the neurological conditions. We will primarily focus on Fyn-mediated signaling pathways involved in neuronal differentiation and plasticity that have been subjected to considerable attention lately, opening the fascinating scenario to target Fyn TK for the development of potential therapeutic interventions for the treatment of CNS injuries and certain neurodegenerative disorders like Alzheimer's disease.