The most common form of DNA is a right-handed helix, the B-form DNA. DNA can also adopt a variety of alternative conformations, termed non-B-form DNA secondary structures, including the G-quadruplex (G4). Furthermore, non-canonical RNA G4 secondary structures are also observed. Recent bioinformatics analysis revealed genomic positions of G4. In addition, G4 formation may be associated with various biological functions, including DNA replication, transcription, epigenetic modification, and RNA metabolism. In this review, we focus on G4 structures in neuronal functions, which may have important roles reveal mechanisms underlying neurological disorders. In addition, we discuss the potential of G4s as a therapeutic target for neurological diseases.

Accumulation of insoluble alpha-synuclein (αS) is a pathological hallmark of some progressive neurodegenerative diseases including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed synucleinopathies. In diseased brain, αS forms β-sheet-rich amyloid fibrils and it is accumulated in neurons or glial cells. A growing body of evidence suggests that spreading of αS pathology occur by prion-like propagation mechanisms. Our study revealed that intracerebral injection of synthetic αS amyloid fibrils into wild-type mice induced prion-like propagation of αS pathology at 1 month post injection, while injection of soluble αS did not induce αS pathology. Furthermore, injection of αS amyloid fibrils into αS knockout mice failed to induce any pathologies. We also have demonstrated that intracerebral injection of αS amyloid fibrils into small primates, adult common marmosets, resulted in spreading of αS pathologies and loss of TH-positive neurons. These in vivo experiments clearly indicate that αS amyloid fibrils has prion-like properties and it propagates through neural networks. The underlying mechanisms of αS propagation are poorly understood, however, αS propagation model animals would be useful in elucidating pathogenetic mechanisms and developing disease-modifying drugs for sporadic synucleinopathies.

Sleep abnormality such as frequent nocturnal arousal and decreased deep non-REM (rapid-eye-movement) sleep is a prevalent but under-recognized symptom that affects patients with various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). In contrast to the conventional understanding that the sleep abnormality in these patients is caused by AD or PD pathology in the brain regions regulating sleep-wake or circadian rhythm, various epidemiological studies have demonstrated the association of sleep abnormality with an increased risk of these diseases. Through various recent studies using relevant animal models to test the causal relationship between sleep abnormality and neurodegenerative diseases, the recent concept of a bidirectional relationship between sleep abnormality and neurodegenerative diseases was established. However, whether therapeutic interventions against sleep abnormality would modify the disease course of neurodegenerative diseases remains unknown. In this review, we will first provide an overview of previous studies that link neurodegenerative diseases and sleep abnormality, mainly focusing on the sleep abnormality in patients with AD. We will then introduce the studies that examined the causal relationship between sleep abnormality and neurodegenerative diseases. Finally, we will discuss possible mechanisms underlying the bidirectional relationship between sleep abnormality and neurodegenerative diseases. A better understanding of these mechanisms would lead to the development of novel pharmacological and/or non-pharmacological treatments that would modify the disease course of neurodegenerative diseases through targeting the processes related to sleep abnormality in the patients of neurodegenerative diseases.

Neurodegenerative diseases are caused by progressive degeneration of specific neurons. To overcome neurodegenerative diseases, the exploitation of preventive drugs is strongly expected, since impaired neurons are not regenerated by drugs. Spinocerebellar ataxia (SCA) is a group of dominantly inherited neurodegenerative diseases and is characterized by the progressive cerebellar ataxia. To date, SCA is classified into SCA1-48 by the variance of causal genes. Since SCA patients are commonly characterized by cerebellar ataxia and atrophy of cerebellum, it is possible that there are common pathogenic mechanisms in SCAs. However, there are not any shared functions among SCA-causing proteins. Cerebellar Purkinje cells (PCs) are sole output neurons from cerebellar cortexes, crucial for cerebellar functions and characterized highly branched dendrites. During the exploration of the molecular pathogenesis of several SCA-causing proteins, we found that several SCA-causing proteins commonly trigger the impairment of dendritic development of primary cultured cerebellar PCs. Dendritic shrinkage of cerebellar PCs has been observed and is considered to be related to the motor dysfunction in several SCA model mice. Therefore, we assume that impaired dendritic development of cultured cerebellar Purkinje cells is one of the common phenotypes of SCA in vitro and that cultured PCs expressing SCA-causing proteins could be in vitro SCA models. This SCA model would be useful for the efficient exploration of novel preventive drugs against various types of SCAs.

Iron is an essential trace metal element for maintaining vital functions, and it is involved in hemoglobin synthesis, redox reaction, enzyme activity, cell proliferation and apoptosis in various cells. Iron deficient-related diseases represented anemia are well-known, on the other hand, iron overload disease has attracted little attention. Excessive iron produces hydroxyl radicals via Fenton/Haber-Weiss reaction, causing organ damage in hereditary iron overload diseases. Additionally, it has been clarified that iron accumulation is involved in the pathological conditions even in metabolic diseases thought to be unrelated to iron so far. Therefore, the role of iron in the living body has been raised attention again. Recent studies have reported that body iron content is associated with both obesity and diabetes, and iron might be an aggravating factor of obesity and diabetes. We have revealed that iron chelating agent reduced oxidative stress and inflammation, suppressing the development of adipose hypertrophy in KKAy mice. Dietary iron restriction also diminishes oxidative stress, leading to the inhibition of increased albuminuria excretion and glomerular lesions in db/db mice. In this review, we give an outline of the role of iron on obese and diabetes, and diabetic kidney disease, and present the possibility of application to treatment with iron regulation in those disorders.

Iron is the most abundant transition metal in our body and plays various pivotal roles in our lives including oxygen transport, energy production, and metabolic reactions. At the same time, an excess amount of iron may cause cellular damages through undesired oxidative reactions due to the high redox activity of Fe ion. We have developed the several fluorescent probes which can detect Fe(II) ion selectively with fluorescence enhancement to understand both the physiological and pathological contributions of Fe ion in living systems. These fluorescent probes worked in an aqueous buffer, living cells, and histochemical-stained samples (Chem Sci. 2013;4:1250, Chem Sci. 2017;8:4858, Free Radic Res. 2014;48:990, Sci Rep. 2017;7:10621). We established a color series of Fe(II)-selective fluorescent probes from blue to deep-red, which were applied to organelle-targeted fluorescent probes for mitochondria, lysosome, and endoplasmic reticulum. Herein, I would like to focus on fluorescence imaging study about the alteration of labile Fe(II) level in each organelle during ferroptosis, iron-dependent cell death, by using the various organelle-targeted fluorescent probes of Fe(II).

Zinc (Zn) is one of the essential trace elements required for human developments and it plays an important role in the maintenance of numerous tissue homeostasis. The amount of Zn levels was below the constant level which induced the various harmful health effects such as impaired growth, hair loss, taste disturbance, anorexia. Maintenance of Zn homeostasis in body mainly depends on two families of Zn transporters; Zrt- and Irt-like proteins (ZIPs), and Zinc transporters (ZnTs). Some studies based on the gene knock-out mice and human genetic analysis have been reported the relationship between zinc transporters and human diseases. Recent studies have shown that Zn transporter-mediated Zn ion behaves as a signaling factor, called Zn signal, that exerts a multiple function in cellular events. In this review article we describe important physiological roles of Zn transporters and their contribution at the molecular, biochemical, and genetic levels underlying the mechanisms of human diseases.

Down syndrome caused by triplication of human chromosome 21 (HSA21) is the most frequent aneuploidy, resulting in mental retardation, intellectual disability and accelerated aging. Individuals with DS are at an increased risk of developing Alzheimer’s disease (AD)-like dementia, with up to 75% of DS people in their 60s developing dementia. Oxidative stress is widely accepted as a mechanism underlying a number of DS symptoms, such as accelerated aging and cognitive decline. Superoxide disumutase 1 (Sod1) and amiloyd precursor protein (App) genes are suggested as the candidate genes in HSA21 underlying the enhanced oxidative stress in individuals with DS. However, we previously demonstrated that the Ts1Cje mouse model, which has a normal copy number of both candidate genes, also shows enhanced oxidative stress, suggesting that triplicated genes other than Sod1 and App likely enhance oxidative stress in the brain of DS people. To identify the molecules with enhanced oxidative stress in Ts1Cje mice, we performed several -omics analyses. Recently, we showed that copper was accumulated in the brain of adult Ts1Cje mice in an analysis using inductively coupled plasma mass spectrometry (ICP-MS), and a low-copper diet was able to improve the elevated levels of copper. The low-copper diet also resolved some anomalies, such as the enhanced oxidative stress, accumulation of phosphorylated tau and low anxiety. These findings suggest that the accumulation of copper in the DS brain may be a therapeutic target for ameliorating a number of abnormal phenotypes in individuals with DS.

Central nervous system (CNS) inflammation causes severe neurological dysfunction, such as motor, sensory, and cognitive impairments. One of the reasons for the developing disease depends on the damage of neuronal network, a predominant feature of many CNS diseases. Therefore, protection and/or regeneration of damaged neuronal network after injury is considered to be useful for treating neurological diseases; however, the mechanism of protection and regeneration of neuronal network is not fully elucidated. In this paper, I describe our recent findings about the mechanism that disrupt and regenerate neuronal network by using animal model of multiple sclerosis. I also introduce the key molecules which is involved in inflammation, neurovascular interaction, and systemic regulation. These findings have a potential to contribute develop the new therapies for treating neurological disease.

MPS (microphysiological system) is in-vitro cell-culture environment, which is precisely maintained in a micro space manufactured using MEMS (micro electro mechanical systems) technology, to derive in-vivo like functions from human cells. From the viewpoint of pharmacokinetics, it can be considered as a wet PBPK/PD simulator consisting of the micro organs (cell culture units) connected each other with a circulating medium, which mimic the organs responsible for the drug’s ADME (absorption-distribution-metabolism-elimination). In this review, we identify two types of the cell culture units consisting of the MPS for pharmacokinetics, and overview the characteristics of each type. Then, we discuss about the technical requirements needed for the cell culture unit from the point of view of both cell-culture environmental design and cell function, and introduce the world-wide current situation of the commercialization of the MPS.

Mirogabalin, a novel ligand for the α₂δ subunit of voltage-gated calcium channels, has been approved for the treatment of peripheral neuropathic pain including painful diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN) in Japan. Mirogabalin showed potent and selective binding affinities for the α₂δ subunits, and slower dissociation rates for the α₂δ-1 subunit than for the α₂δ-2 subunit. It also showed potent and long-lasting analgesic effects in rat models of neuropathic pain, and wider safety margins for the central nervous system side effects. A pharmacological study using mutant mice demonstrated that the analgesic effects of mirogabalin were mediated by binding of the drug to the α₂δ-1 subunit, not the α₂δ-2 subunit. The pharmacological properties of mirogabalin can be associated with its unique binding characteristics. The bioavailability of mirogabalin is high and its plasma exposure increases dose-proportionally. Mirogabalin is mainly excreted via the kidneys in an unchanged form, thus, mirogabalin has a low possibility of undergoing drug–drug interaction, while dose adjustment based on the creatinine clearance level is specified in patients with renal impairment. In double-blind, placebo-controlled phase 3 studies in Asian patients with DPNP and PHN, mirogabalin showed significant and dose-dependent pain relief, and all tested doses of mirogabalin were well tolerated. In summary, mirogabalin has a balanced efficacy versus safety profile, and can provide an alternative therapeutic option for the treatment of peripheral neuropathic pain.