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Repulsive guidance molecule-a (RGMa), a glycosylphosphatidylinositol-anchored membrane protein, has diverse functions in axon guidance, cell patterning, and cell survival. Inhibition of RGMa attenuates pathological dysfunction in animal models of central nervous system (CNS) diseases including spinal cord injury, multiple sclerosis, and neuromyelitis optica. Here, we examined whether antibody-based inhibition of RGMa had therapeutic effects in a mouse model of Parkinson’s disease (PD). We treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found increased RGMa expression in the substantia nigra (SN). Intraventricular, as well as intravenous, administration of anti-RGMa antibodies reduced the loss of tyrosine hydroxylase (TH)-positive neurons and accumulation of Iba1-positive microglia/macrophages in the SN of MPTP-treated mice. Selective expression of RGMa in TH-positive neurons in the SN-induced neuronal loss/degeneration and inflammation, resulting in a progressive movement disorder. The pathogenic effects of RGMa overexpression were attenuated by treatment with minocycline, which inhibits microglia and macrophage activation. Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia. Our observations suggest that the upregulation of RGMa is associated with the PD pathology; furthermore, inhibitory RGMa antibodies are a potential therapeutic option.

Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine. In clinical practice, GJG is effective against neuropathic pain and hypersensitivity induced by chemotherapy or diabetes. In our previous study using a chronic constriction injury mouse model, we showed that GJG inhibited microglia activation by suppressing the expression of tumor necrosis factor-α (TNF-α) and p38 mitogen-activated protein kinase (p38 MAPK) in the peripheral nervous system. To investigate whether GJG can suppress inflammation in the central nervous system (CNS) in the context of neurological disorders, we examined the effect of GJG on the activation of resident glial cells and on p38-TNF signaling in two mouse models of neurological disorders: the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease. GJG administration relieved the severity of clinical EAE symptoms and MPTP-induced inflammation by decreasing the number of microglia and the production of TNF-α in the spinal cord of EAE mice and the substantia nigra of MPTP-treated mice. Accordingly, GJG suppressed the phosphorylation of p38 in glial cells of these two mouse models. We conclude that GJG attenuates inflammation of the CNS by suppressing glial cell activation, followed by a decrease in the production of TNF-α via p38-TNF signaling. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00948-w) contains supplementary material, which is available to authorized users.

In addition to muscle nicotinic acetylcholine receptor (AChR) and muscle-specific kinase (MuSK), low-density lipoprotein receptor (Lrp4) has recently been discovered to be a novel target antigen among patients with seronegative myasthenia gravis (MG). We herein report the findings of a 62-year-old patient who showed positivity for anti-MuSK, anti-Lrp4, and anti-titin antibodies. The patient developed MG crisis following a 10-year history of intermittent double vision with ptosis, and a 7-year history of dropped head. Our detailed clinical, laboratory, and therapeutic descriptions highlight its unique characteristics of anti-MuSK-antibody positive MG accompanied by anti-Lrp4 and anti-titin antibodies.

Biotinidase is essential for the recycling of biotin, which serves as a coenzyme for four biotin-dependent carboxylases involved in fatty acid synthesis, gluconeogenesis, and amino acid catabolism.1 Biotinidase deficiency (BD) is a rare, autosomal recessively inherited disorder that if untreated can cause neurological symptoms including seizures, hypotonia, respiratory abnormalities, and vison/hearing loss, especially in countries that do not screen newborns.2 This condition is readily treatable with the administration of biotin, but delays in diagnosis and initiation of therapy can result in irreversible neurological defects. Typically, patients with BD are diagnosed as newborns and treated with biotin administration throughout childhood. Although there are several case reports of adult-onset BD, most patients show some initial symptoms by their 20s or 30s.3, 4 Here, we report an autopsy case of a patient who was 63 years old at the onset of acutely progressing leukoencephalopathy that was subsequently diagnosed as BD.

ObjectiveTo investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS.MethodsSerum ADMA levels of patients with sporadic ALS (n = 68) and disease control patients (n = 54) were measured using liquid chromatography-tandem mass spectrometry. Serum samples were obtained at the time of patient registration for diagnosis. Correlations of ADMA level and other markers (nitric oxide [NO] and neurofilament light chain [NFL] levels) were analyzed. Changes in the ALS Functional Rating Scale–Revised (ALSFRS-R) score from the onset of disease (ALSFRS-R preslope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan–Meier analysis.ResultsThe concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001), and was independently associated with the ALSFRS-R preslope (r = 0.505. p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF NfL level (r = 0.456, p = 0.0002) but not with NO level (r = 0.194, p = 0.219).ConclusionADMA level is an independent biomarker of ALS disease progression and prognosis, and reflects the degree of motor neuron degeneration. The increased ADMA level in ALS patients was not associated with the inhibition of NO production.

While the initial causes of Parkinson's disease (PD) are not clearly defined, iron deposition has long been implicated in the pathogenesis of PD. The substantia nigra of PD patients, where the selective loss of dopaminergic neurons occurs, show a fairly selective and significant elevation in iron contents. However, the question remains whether iron deposition represents the initiation cause or merely the consequence of nigral degeneration. Here, we describe existing findings regarding the interaction of iron with neuromelanin and alpha synuclein, the iron deposition in experimental animal model of PD and sporadic and familial PD patients, and the treatment option involving the use of iron chelators for targeting the aberration of iron level in brain. This review may provide us a better understanding of the role of iron in PD to address the question of cause or consequence.

Summary Go-sha-jinki-gan (GJG), a traditional Japanese herbal medicine has a clinical implication to alleviate age-related symptoms, especially in some motor disorders. However, the scientific evidence is limited, and there is a possibility to expand the medical application range of GJG. Using senescence-accelerated mice, our group showed that GJG exerted an effect to prevent sarcopenia, the aged-related loss of skeletal muscle. Because muscular dystrophy is characterized by a progressive loss of skeletal muscle, we examined the effects of GJG on a mouse model of muscular dystrophy. Using a newly established mouse model for Duchenne muscular dystrophy (DMD), DBA/2-mdx, we showed that GJG significantly increased the body and skeletal muscle weights in comparison to the control DBA/2-mdx mice, regardless of gender. The increased skeletal muscle mass resulted from an increment in the myofiber size, but not from the myofiber number. Both the skeletal muscle regenerative ability and the accumulation of fibrosis (the dystrophic pathology) in GJG-fed DBA/2-mdx mice were comparable to those in control DBA/2-mdx mice, suggesting that the cellular target of GJG is myofibers, with no contribution from the muscle satellite cells neither in an direct nor in an indirect manner. Taken together, GJG increased the skeletal muscle mass in a mouse model of muscular dystrophy, in addition to our previously tested sarcopenia mouse model.

Neuropathic pain is a chronic condition that occurs frequently after nerve injury and induces hypersensitivity or allodynia characterized by aberrant neuronal excitability in the spinal cord dorsal horn. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) is a modulator of neurite outgrowth, axon pathfinding, and cell adhesion, which is upregulated in the dorsal horn following peripheral nerve injury. However, the function of FLRT3 in adults remains unknown. Therefore, we aimed to investigate the involvement of spinal FLRT3 in neuropathic pain using rodent models. In the dorsal horns of male rats, FLRT3 protein levels increased at day 4 after peripheral nerve injury. In the DRG, FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated Flrt3 transcription in the DRG but not in the spinal cord. Intrathecal administration of FLRT3 protein to naive rats induced mechanical allodynia and GluN2B phosphorylation in the spinal cord. DRG-specific FLRT3 overexpression using adeno-associated virus also produced mechanical allodynia. Conversely, a function-blocking FLRT3 antibody attenuated mechanical allodynia after partial sciatic nerve ligation. Therefore, FLRT3 derived from injured DRG neurons increases dorsal horn excitability and induces mechanical allodynia. SIGNIFICANCE STATEMENT Neuropathic pain occurs frequently after nerve injury and is associated with abnormal neuronal excitability in the spinal cord. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) regulates neurite outgrowth and cell adhesion. Here, nerve injury increased FLRT3 protein levels in the spinal cord dorsal root, despite the fact that Flrt3 transcripts were only induced in the DRG. FLRT3 protein injection into the rat spinal cord induced mechanical hypersensitivity, as did virus-mediated FLRT3 overexpression in DRG. Conversely, FLRT3 inhibition with antibodies attenuated mechanically induced pain after nerve damage. These findings suggest that FLRT3 is produced by injured DRG neurons and increases neuronal excitability in the dorsal horn, leading to pain sensitization. Neuropathic pain induction is a novel function of FLRT3.

Many nervous system disorders are minimally responsive to existing treatments but they are potential candidates for gene therapy, an approach that can correct the genetic abnormalities contributing to its pathogenesis at molecular level. Gene therapy involves either the introduction of a replacement allele into cells to compensate for loss of gene function or the silencing of dominant mutant allele that is pathologic to cells.This review discusses the currently available gene therapy techniques, potential problems derived from gene therapy strategies and the recent development of gene therapy to treat neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and strokes.Gene therapy may revolutionize the treatment of neurological disorders in the coming decades but there are still great challenges ahead. The strength of gene therapy has been emphasized in the overexpression of therapeutic genes. However, in a number of dominantly inherited nervous system diseases, the ideal therapeutic goal would be to inhibit the expression of disease-causing allele. Gene silencing strategies by single-stranded antisense oligonucleotides and RNA interference represent a major breakthrough. Clinical trials using these approaches for dominant diseases are likely to be implemented in the near future.

We herein report the case of a 72-year-old man demonstrating myasthenia gravis (MG) with a dropped head and acute respiratory insufficiency. There was no ocular, bulbar, or limb involvement. The patient was seronegative for anti-acetylcholine receptor (AChR) antibodies and anti-muscle-specific tyrosine kinase (MuSK) antibodies. Subsequent tests showed seropositivity for anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies. The addition of steroid pulse therapy resulted in a full remission of his respiratory symptoms. This presentation suggests that LRP4-positive MG should be considered in the differential diagnosis of patients presenting with acute respiratory insufficiency without either cranial or limb involvement.

Background Alternative medicine is noted for its clinical effect and minimal invasiveness in the treatment of neuropathic pain. Go-sha-jinki-Gan, a traditional Japanese herbal medicine, has been used for meralgia and numbness in elderly patients. However, the exact mechanism of GJG is unclear. This study aimed to investigate the molecular mechanism of the analgesic effect of GJG in a chronic constriction injury model. Results GJG significantly reduced allodynia and hyperalgesia from the early phase (von Frey test, p

A 54-year-old woman with no medical history presented with left hemiparesis and hemianopsia. Brain MRI showed an extensive lesion without enhancement in the right parietal lobe, followed by rapid cavity formation (figure 1). Brain biopsy performed 55 days after disease onset revealed decreased glial fibrillary acidic protein and aquaporin-4 (AQP4) immunoreactivity, though we could not show the activated complement due to the paucity of the sample (figure 2).

Fourteen patients in a healthcare center for the elderly (100 beds) at Hokushin General Hospital contracted influenza due to influenza virus A in February 2006. To prevent the spread of the disease, the preventive administration of oseltamivir was conducted for 44 non-infected patients at a daily dose of 1 capsule daily for a period of 1 to 3 days. There were no new cases of influenza during the 1 week period from the start of the administering oseltamivir suggesting that this method of preventing influenza was more successful than influenza vaccination.

We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content.