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Medicina (Kaunas, Lithuania) Jun 2023: Parkinson's disease (PD) is a clinically heterogeneous disorder with poorly understood pathological contributing factors. Depression presents one of the most frequent... (Review)
Review
: Parkinson's disease (PD) is a clinically heterogeneous disorder with poorly understood pathological contributing factors. Depression presents one of the most frequent non-motor PD manifestations, and several genetic polymorphisms have been suggested that could affect the depression risk in PD. Therefore, in this review we have collected recent studies addressing the role of genetic factors in the development of depression in PD, aiming to gain insights into its molecular pathobiology and enable the future development of targeted and effective treatment strategies. : we have searched PubMed and Scopus databases for peer-reviewed research articles published in English (pre-clinical and clinical studies as well as relevant reviews and meta-analyses) investigating the genetic architecture and pathophysiology of PD depression. : in particular, polymorphisms in genes related to the serotoninergic pathway (sodium-dependent serotonin transporter gene, , tryptophan hydrolase-2 gene, ), dopamine metabolism and neurotransmission (dopamine receptor D3 gene, , aldehyde dehydrogenase 2 gene, , neurotrophic factors (brain-derived neurotrophic factor gene, ), endocannabinoid system (cannabinoid receptor gene, CNR1), circadian rhythm (thyrotroph embryonic factor gene, ), the sodium-dependent neutral amino acid transporter B(0)AT2 gene, ), and genetic locus were detected as altering susceptibility to depression among PD patients. However, polymorphisms in the dopamine transporter gene (), monoamine oxidase A () and B () genes, catechol-O-methyltransferase gene (), , and have not been related to PD depression. : the specific mechanisms underlying the potential role of genetic diversity in PD depression are still under investigation, however, there is evidence that they may involve neurotransmitter imbalance, mitochondrial impairment, oxidative stress, and neuroinflammation, as well as the dysregulation of neurotrophic factors and their downstream signaling pathways.
Topics: Humans; Parkinson Disease; Catechol O-Methyltransferase; Depression; Polymorphism, Genetic; Nerve Growth Factors; Genetic Predisposition to Disease; Aldehyde Dehydrogenase, Mitochondrial; Serotonin Plasma Membrane Transport Proteins; Nerve Tissue Proteins; Amino Acid Transport Systems, Neutral
PubMed: 37374342
DOI: 10.3390/medicina59061138 -
Frontiers in Cellular and Infection... 2023Copper, a vital element in various physiological processes, is transported from the gastrointestinal tract to tissues and cells through diverse copper transporters.... (Review)
Review
Copper, a vital element in various physiological processes, is transported from the gastrointestinal tract to tissues and cells through diverse copper transporters. Among these transporters, ATP7A and ATP7B play significant roles in regulating systemic copper metabolism and exhibit precise regulation in their intracellular trafficking. These transporters undergo dynamic shuttling between the trans-Golgi network (TGN) and the plasma membrane via the endocytic recycling mechanism, which involves the retromer and other associated factors. Interestingly, the antimicrobial attribute of copper implies a potential connection between microbial infection and copper metabolism. Several microbes, including , , Influenza A virus (IAV) and Zika virus (ZIKV) have been observed to impact the regulatory mechanisms of ATP7A/B, either directly or indirectly, as a means of survival. This review summarizes the key features and trafficking mechanisms of the copper transporters ATP7A/B, and examines the intricate interplay between microbes and copper metabolism. Ultimately, it highlights how microbes can perturb copper homeostasis through interactions with host factors, offering valuable insights into the mechanistic aspects of host-microbe interactions.
Topics: Humans; Copper; Adenosine Triphosphatases; Zika Virus Infection; Cation Transport Proteins; Zika Virus; Copper Transport Proteins; Copper-Transporting ATPases; Peptide Fragments
PubMed: 38106478
DOI: 10.3389/fcimb.2023.1267931 -
Cells Apr 2023Cell-penetrating peptides (CPPs) are short peptides with the ability to translocate through the cell membrane to facilitate their cellular uptake. CPPs can be used as... (Review)
Review
Cell-penetrating peptides (CPPs) are short peptides with the ability to translocate through the cell membrane to facilitate their cellular uptake. CPPs can be used as drug-delivery systems for molecules that are difficult to uptake. Ocular drug delivery is challenging due to the structural and physiological complexity of the eye. CPPs may be tailored to overcome this challenge, facilitating cellular uptake and delivery to the targeted area. Retinal diseases occur at the posterior pole of the eye; thus, intravitreal injections are needed to deliver drugs at an effective concentration in situ. However, frequent injections have risks of causing vision-threatening complications. Recent investigations have focused on developing long-acting drugs and drug delivery systems to reduce the frequency of injections. In fact, conjugation with CPP could deliver FDA-approved drugs to the back of the eye, as seen by topical application in animal models. This review summarizes recent advances in CPPs, protein/peptide-based drugs for eye diseases, and the use of CPPs for drug delivery based on systematic searches in PubMed and clinical trials. We highlight targeted therapies and explore the potential of CPPs and peptide-based drugs for eye diseases.
Topics: Animals; Cell-Penetrating Peptides; Eye; Drug Delivery Systems; Biological Transport; Pharmaceutical Preparations; Eye Diseases
PubMed: 37048144
DOI: 10.3390/cells12071071 -
Microbiology (Reading, England) Dec 2022Peptide transporters play important nutritional and cell signalling roles in which are pronounced during stationary phase adaptations and development. Three...
Peptide transporters play important nutritional and cell signalling roles in which are pronounced during stationary phase adaptations and development. Three high-affinity ATP-binding cassette (ABC) family transporters are involved in peptide uptake - the oligopeptide permease (Opp), another peptide permease (App) and a less well-characterized dipeptide permease (Dpp). Here we report crystal structures of the extracellular substrate binding proteins, OppA and DppE, which serve the Opp and Dpp systems, respectively. The structure of OppA was determined in complex with endogenous peptides, modelled as Ser-Asn-Ser-Ser, and with the sporulation-promoting peptide Ser-Arg-Asn-Val-Thr, which bind with values of 0.4 and 2 µM, respectively, as measured by isothermal titration calorimetry. Differential scanning fluorescence experiments with a wider panel of ligands showed that OppA has highest affinity for tetra- and penta-peptides. The structure of DppE revealed the unexpected presence of a murein tripeptide (MTP) ligand, l-Ala-d-Glu--DAP, in the peptide binding groove. The mode of MTP binding in DppE is different to that observed in the murein peptide binding protein, MppA, from , suggesting independent evolution of these proteins from an OppA-like precursor. The presence of MTP in DppE points to a role for Dpp in the uptake and recycling of cell wall peptides, a conclusion that is supported by analysis of the genomic context of , which revealed adjacent genes encoding enzymes involved in muropeptide catabolism in a gene organization that is widely conserved in .
Topics: Bacillus subtilis; Peptidoglycan; Bacterial Proteins; Oligopeptides; Membrane Transport Proteins; Escherichia coli; ATP-Binding Cassette Transporters
PubMed: 36748525
DOI: 10.1099/mic.0.001274 -
EMBO Reports Oct 2023Monoamine transporters retrieve serotonin (SERT), dopamine (DAT), and norepinephrine (NET) from the synaptic cleft. Transporter internalization contributes to the...
Monoamine transporters retrieve serotonin (SERT), dopamine (DAT), and norepinephrine (NET) from the synaptic cleft. Transporter internalization contributes to the regulation of their surface expression. Clathrin-mediated endocytosis of plasma membrane proteins requires adaptor protein-2 (AP2), which recruits cargo to the nascent clathrin cage. However, the intracellular portions of monoamine transporters are devoid of a conventional AP2-binding site. Here, we identify a MAD2 (mitotic arrest deficient-2) interaction motif in the C-terminus of SERT, which binds the closed conformation of MAD2 and allows for the recruitment of two additional mitotic spindle assembly checkpoint (SAC) proteins, BubR1 and p31 , and of AP2. We visualize MAD2, BubR1, and p31 in dorsal raphe neurons, and depletion of MAD2 in primary serotonergic rat neurons decreases SERT endocytosis in the soma. Our findings do not only provide mechanistic insights into transporter internalization but also allow for rationalizing why SAC proteins are present in post-mitotic neurons.
Topics: Rats; Animals; Serotonin Plasma Membrane Transport Proteins; Mad2 Proteins; Nuclear Proteins; Cell Cycle Proteins; Adaptor Proteins, Signal Transducing; Endocytosis; Spindle Apparatus; Clathrin
PubMed: 37530743
DOI: 10.15252/embr.202153408 -
American Journal of Physiology. Cell... Jan 2020Cl is the major extracellular (Cl) and intracellular (Cl) anion whose concentration is actively regulated by multiple transporters. These transporters generate Cl... (Review)
Review
Cl is the major extracellular (Cl) and intracellular (Cl) anion whose concentration is actively regulated by multiple transporters. These transporters generate Cl gradients across the plasma membrane and between the cytoplasm and intracellular organelles. [Cl] changes rapidly in response to cell stimulation and influences many physiological functions, as well as cellular and systemic homeostasis. However, less appreciated is the signaling function of Cl. Cl interacts with multiple proteins to directly modify their activity. This review highlights the signaling function of Cl and argues that Cl is a bona fide signaling ion, a function deserving extensive exploration.
Topics: Animals; Anion Exchange Protein 1, Erythrocyte; Anion Transport Proteins; Chlorides; Gene Expression Regulation; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Receptors, Purinergic P2X7; Signal Transduction; Sulfate Transporters
PubMed: 31693396
DOI: 10.1152/ajpcell.00354.2019 -
Biochimica Et Biophysica Acta.... Jun 2020In the mitochondria of healthy cells, Apoptosis-Inducing factor (AIF) is required for the optimal functioning of the respiratory chain machinery, mitochondrial... (Review)
Review
In the mitochondria of healthy cells, Apoptosis-Inducing factor (AIF) is required for the optimal functioning of the respiratory chain machinery, mitochondrial integrity, cell survival, and proliferation. In all analysed species, it was revealed that the downregulation or depletion of AIF provokes mainly the post-transcriptional loss of respiratory chain Complex I protein subunits. Recent progress in the field has revealed that AIF fulfils its mitochondrial pro-survival function by interacting physically and functionally with CHCHD4, the evolutionarily-conserved human homolog of yeast Mia40. The redox-regulated CHCHD4/Mia40-dependent import machinery operates in the intermembrane space of the mitochondrion and controls the import of a set of nuclear-encoded cysteine-motif carrying protein substrates. In addition to their participation in the biogenesis of specific respiratory chain protein subunits, CHCHD4/Mia40 substrates are also implicated in the control of redox regulation, antioxidant response, translation, lipid homeostasis and mitochondrial ultrastructure and dynamics. Here, we discuss recent insights on the AIF/CHCHD4-dependent protein import pathway and review current data concerning the CHCHD4/Mia40 protein substrates in metazoan. Recent findings and the identification of disease-associated mutations in AIF or in specific CHCHD4/Mia40 substrates have highlighted these proteins as potential therapeutic targets in a variety of human disorders.
Topics: Apoptosis Inducing Factor; Cysteine; Disulfides; Electron Transport Complex I; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Mutation; Protein Transport; Saccharomyces cerevisiae
PubMed: 32105825
DOI: 10.1016/j.bbadis.2020.165746 -
Oxidative Medicine and Cellular... 2022Overcoming blood-brain barrier (BBB) to improve brain bioavailability of therapeutic drug remains an ongoing concern. Prodrug is one of the most reliable approaches for... (Review)
Review
Overcoming blood-brain barrier (BBB) to improve brain bioavailability of therapeutic drug remains an ongoing concern. Prodrug is one of the most reliable approaches for delivering agents with low-level BBB permeability into the brain. The well-known antioxidant capacities of cysteine (Cys) and its vital role in glutathione (GSH) synthesis indicate that Cys-based prodrug could potentiate therapeutic drugs against oxidative stress-related neurodegenerative disorders. Moreover, prodrug with Cys moiety could be recognized by the excitatory amino acid transporter 3 (EAAT3) that is highly expressed at the BBB and transports drug into the brain. In this review, we summarized the strategies of crossing BBB, properties of EAAT3 and its natural substrates, Cys and its donors, and Cys donor-based brain-targeting prodrugs by referring to recent investigations. Moreover, the challenges that we are faced with and future research orientations were also addressed and proposed. It is hoped that present review will provide evidence for the pursuit of novel Cys donor-based brain-targeting prodrug.
Topics: Animals; Antioxidants; Biological Transport; Blood-Brain Barrier; Cysteine; Excitatory Amino Acid Transporter 3; Glutathione; Humans; Neurodegenerative Diseases; Oxidative Stress; Permeability; Prodrugs; Signal Transduction
PubMed: 35251474
DOI: 10.1155/2022/4834117 -
Cells Dec 2022With the ability to transport cargo molecules across cell membranes with low toxicity, cell-penetrating peptides (CPPs) have become promising candidates for next... (Review)
Review
With the ability to transport cargo molecules across cell membranes with low toxicity, cell-penetrating peptides (CPPs) have become promising candidates for next generation peptide-based drug delivery vectors. Over the past three decades since the first CPP was discovered, a great deal of work has been done on the cellular uptake mechanisms and the applications for the delivery of therapeutic molecules, and significant advances have been made. But so far, we still do not have a precise and unified understanding of the structure-activity relationship of the CPPs. Molecular dynamics (MD) simulations provide a method to reveal peptide-membrane interactions at the atomistic level and have become an effective complement to experiments. In this paper, we review the progress of the MD simulations on CPP-membrane interactions, including the computational methods and technical improvements in the MD simulations, the research achievements in the CPP internalization mechanism, CPP decoration and coupling, and the peptide-induced membrane reactions during the penetration process, as well as the comparison of simulated and experimental results.
Topics: Cell-Penetrating Peptides; Molecular Dynamics Simulation; Biological Transport; Cell Membrane; Drug Delivery Systems
PubMed: 36552778
DOI: 10.3390/cells11244016 -
Biochemical Society Transactions Apr 2020Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an... (Review)
Review
Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an important role in regulating the uptake of nutrients and vitamins from the diet, and in controlling the distribution of their metabolic intermediates within the cell. Several SLC families also play an important role in drug transport and strategies are being developed to hijack SLC transporters to control and regulate drug transport within the body. Through the addition of amino acid and peptide moieties several novel antiviral and anticancer agents have been developed that hijack the proton-coupled oligopeptide transporters, PepT1 (SCL15A1) and PepT2 (SLC15A2), for improved intestinal absorption and renal retention in the body. A major goal is to understand the rationale behind these successes and expand the library of prodrug molecules that utilise SLC transporters. Recent co-crystal structures of prokaryotic homologues of the human PepT1 and PepT2 transporters have shed important new insights into the mechanism of prodrug recognition. Here, I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition.
Topics: Animals; Biological Transport; Crystallography, X-Ray; Drug Design; Humans; Oligopeptides; Peptide Transporter 1; Prodrugs; Symporters; Valacyclovir; Valganciclovir
PubMed: 32219385
DOI: 10.1042/BST20180302