Introduction to the multi-author review on methylation in cellular physiology Abstract Protein post-translational modifications (PTMs) have long been a topic of intensive investigation. Covalent additions to the 20 genetically encoded amino acids can alter protein interactions and can even change enzymatic function. In eukarya, PTMs can amplify both the complexity and functional paradigms of the cellular environment. Therefore, PTMs have been of substantial research interest, both for understanding fundamental mechanisms and to provide insight into drug design. Indeed, targeting proteins involved in writing, reading, and erasing PTMs important for human pathologies are some of the most fruitful avenues of drug discovery. In this multi-author review, we explore exciting new work on lysine and arginine methylation, molecular and structural understanding of some of the lysine and arginine methyltransferases (KMTs and PRMTs, respectively), novel insights into nucleic acid methylation, and how the enzymes responsible for writing these PTMs and readers responsible for recognizing these PTMs could be drugged. Here, we introduce the background and the topics covered in this issue.

Metalloproteinases in nervous system function and pathology: introduction Abstract This multi-author review in CMLS includes ten articles that provide an update of current knowledge on the role of metalloproteinases in the physiology and pathology of the central nervous system. The collection covers a wide range of situations in which matrix metalloproteinases, adamalysins and meprins are regulated and in turn regulate substrates or signalling pathways involved in: nervous system development, learning and memory, neuroinflammation, degeneration and repair after traumatic and ischemic injury or neurodegenerative mechanisms underlying retinopathies, psychiatric and neurodegenerative disorders. The authors also argue that these proteinases can be considered in some cases as biomarkers or potential therapeutic targets for diseases of the nervous system. Overall, metalloproteinases are placed among the key factors that can help us better understand the cellular and molecular processes that govern neuropathophysiology and implement the strategies that result from this knowledge to open up much-needed treatment opportunities.

Functions of ‘A disintegrin and metalloproteases (ADAMs)’ in the mammalian nervous system Abstract ‘A disintegrin and metalloproteases’ (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer’s disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.

NEAT1 regulates neuroglial cell mediating Aβ clearance via the epigenetic regulation of endocytosis-related genes expression Abstract The accumulation of intracellular β-amyloid peptide (Aβ) is important pathological characteristic of Alzheimer’s disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aβ clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.

Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level Abstract Protein arginine methyltransferases (PRMTs) catalyze the methyl transfer to the arginine residues of protein substrates and are classified into three major types based on the final form of the methylated arginine. Recent studies have shown a strong correlation between PRMT expression level and the prognosis of cancer patients. Currently, crystal structures of eight PRMT members have been determined. Kinetic and structural studies have shown that all PRMTs share similar, but unique catalytic and substrate recognition mechanism. In this review, we discuss the structural similarities and differences of different PRMT members, focusing on their overall structure, S-adenosyl-l-methionine-binding pocket, substrate arginine recognition and catalytic mechanisms. Since PRMTs are valuable targets for drug discovery, we also rationally classify the known PRMT inhibitors into five classes and discuss their mechanisms of action at the atomic level.

MMPs in learning and memory and neuropsychiatric disorders Abstract Matrix metalloproteinases (MMPs) are a group of over twenty proteases, operating chiefly extracellularly to cleave components of the extracellular matrix, cell adhesion molecules as well as cytokines and growth factors. By virtue of their expression and activity patterns in animal models and clinical investigations, as well as functional studies with gene knockouts and enzyme inhibitors, MMPs have been demonstrated to play a paramount role in many physiological and pathological processes in the brain. In particular, they have been shown to influence learning and memory processes, as well as major neuropsychiatric disorders such as schizophrenia, various kinds of addiction, epilepsy, fragile X syndrome, and depression. A possible link connecting all those conditions is either physiological or aberrant synaptic plasticity where some MMPs, e.g., MMP-9, have been demonstrated to contribute to the structural and functional reorganization of excitatory synapses that are located on dendritic spines. Another common theme linking the aforementioned pathological conditions is neuroinflammation and MMPs have also been shown to be important mediators of immune responses.

Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia Abstract In addition to their modulation through de novo expression and degradation, surface levels of chemokine receptors are tuned by their ligand-dependent recycling to the plasma membrane, which ensures that engaged receptors become rapidly available for further rounds of signaling. Dysregulation of this process contributes to the pathogenesis of chronic lymphocytic leukemia (CLL) by enhancing surface expression of chemokine receptors, thereby favoring leukemic cell accumulation in the protective niche of lymphoid organs. In this review, we summarize our current understanding of the process of chemokine receptor recycling, focusing on the impact of its dysregulation in CLL.

Matrix metalloproteinase signals following neurotrauma are right on cue Abstract Neurotrauma, a term referencing both traumatic brain and spinal cord injuries, is unique to neurodegeneration in that onset is clearly defined. From the perspective of matrix metalloproteinases (MMPs), there is opportunity to define their temporal participation in injury and recovery beginning at the level of the synapse. Here we examine the diverse roles of MMPs in the context of targeted insults (optic nerve lesion and hippocampal and olfactory bulb deafferentation), and clinically relevant focal models of traumatic brain and spinal cord injuries. Time-specific MMP postinjury signaling is critical to synaptic recovery after focal axonal injuries; members of the MMP family exhibit a signature temporal profile corresponding to axonal degeneration and regrowth, where they direct postinjury reorganization and synaptic stabilization. In both traumatic brain and spinal cord injuries, MMPs mediate early secondary pathogenesis including disruption of the blood–brain barrier, creating an environment that may be hostile to recovery. They are also critical players in wound healing including angiogenesis and the formation of an inhibitory glial scar. Experimental strategies to reduce their activity in the acute phase result in long-term neurological recovery after neurotrauma and have led to the first clinical trial in spinal cord injured pet dogs.

Agonist-dependent development of delta opioid receptor tolerance in the colon Abstract The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.

Matrix metalloproteinases in the CNS: interferons get nervous Abstract Matrix metalloproteinases (MMPs) have been investigated in context of chronic inflammatory diseases and demonstrated to degrade multiple components of the extracellular matrix (ECM). However, following several disappointing MMP clinical trials, recent studies have demonstrated unexpected novel functions of MMPs in viral infections and autoimmune inflammatory diseases in unanticipated locations. Thus, MMPs play additional functions in inflammation than just ECM degradation. They can regulate the activity of chemokines and cytokines of the immune response by precise proteolytic processing resulting in activation or inactivation of signaling pathways. MMPs have been demonstrated to cleave multiple substrates of the central nervous systems (CNS) and contribute to promoting and dampening diseases of the CNS. Initially, believed to be solely promoting pathologies, more than 10 MMPs to date have been shown to have protective functions. Here, we present some of the beneficial and destructive roles of MMPs in CNS pathologies and discuss strategies for the use of MMP inhibitors.