Current treatments for Parkinson's disease (PD) are mainly based on medications such as levodopa, dopamine agonists, and inhibitors of dopamine metabolisms. However, it is impossible to halt the progression of the disease. Thus, it is necessary to develop a disease modifying therapy for PD. Therefore, we need the animal models including Drosophila. At present, simple model organisms such as Drosophila are being very useful for the study of genes and pathways involved in a wide range of disorders, mainly due to the similarity of its biological pathways to those of humans. Interestingly, the fly has been successfully used for elucidating the pathogenesis of the diseases. Perry syndrome, involving mutations in the dynein motor component dynactin or p150^Glued, is characterized by TDP–43 pathology in affected brain regions, including the substantia nigra. However, the molecular relationship between p150^Glued and TDP–43 is largely unknown. Here, we report that a reduction in TDP–43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150^G50R in Drosophila. Dopaminergic expression of p150^G50R, which decreases dopamine release, disrupts motor ability and reduces the lifespan of Drosophila. p150^G50R expression also causes aggregation of dense core vesicles (DCVs), which contain monoamines and neuropeptides, and disrupts the axonal flow of DCVs, thus decreasing synaptic strength. The above phenotypes associated with Perry syndrome are improved by the removal of a copy of Drosophila TDP–43 TBPH, thus suggesting that the stagnation of axonal transport by dynactin mutations promotes TDP–43 aggregation and interferes with the dynamics of DCVs and synaptic activities. In this study, regulation of TDP–43 expression could be one strategy for development of new therapies. In addition, Drosophila model could be a useful tool for elucidating of the pathomechanisms of the several genetic diseases.

TAR DNA–binding protein 43kDa (TDP–43) is a hallmark protein for amyotrophic lateral sclerosis (ALS), consisting of ubiquitinated and phosphorylated cytosolic inclusions in affected regions, namely TDP–43 proteinopathy. TDP–43 is physiologically located in the nucleus and plays diverse roles to maintain the RNA homeostasis, including pro–mRNA splicing, microRNA processing, non–coding RNA stabilization, mRNA transport, and the stress granule formation. Multiple cascades, basically causing a loss of these functions, have been proposed as TDP–43–linked ALS pathogenesis ; however, the mislocalization and aggregate formation of TDP–43 is considered to underlie various pathogenic pathways, ultimately leading to motor neuron death. A cell–to–cell spreading theory is attracting huge attention to explain the rapid regional progression of the paralysis, although in vivo evidence is still lacking. Recent knowledge highlights the stress granules as responsible sites of TDP–43 inclusion formation. The stress granules contain mRNA with chains of ribosomes, together with stress granule–related proteins, such as TIA1 and TDP–43, in which RNA translation is inhibited transiently until stress conditions are recovered. The disruption of this reversibility is implicated in the irreversible inclusion formation. A proportion of familial ALS patients carries genetic mutations in the TDP–43 gene, the most of which are concentrated at the carboxyl prion–like domain. Although the pathomechanisms regarding how mutant TDP–43 causes ALS remain elusive, it is reported that mutant TDP–43 impairs proteasome activity, resulting in the accumulation of aberrant TDP–43. Moreover, several genetic mutations other than TDP–43, such as C9ORF72, MATR3, hnRNP1, UBQLN2, STSM1, VCP, and OPTN cause TDP–43 proteinopathy. Importantly, transgenic mice expressing cytosolic TDP–43 show the similar phenotype of ALS, and the inhibition of the transgene restore the paralysis of the mice. These line of evidence indicate the huge potential of misfolded TDP–43 as a therapeutic target. Capturing the early structural conversion to pathogenic forms is a promising therapeutic avenue to overcome ALS.

Neuroinflammation, characterized by activated astrocytes, microglia, infiltrating immune cells, and the subsequent production of inflammatory mediators, is a pathological process involved in the various neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS). Moreover, increasing evidences suggest that activated glial cells and immune cells, the key players of neuroinflammation, contribute to disease progression of ALS by the non–cell autonomous mechanism. Activated microglia produce pro–inflammatory cytokines and other neurotoxic or neuroprotective molecules likely under a control by astrocytes and infiltrated T cells. In the peripheral blood of patients with ALS, immune balance showed to be relatively Th1–dominant with higher level of interferon–γ (IFN–γ). On the other hand, regulatory T cells (Tregs), the number of which is reduced in the peripheral blood of ALS patients, are thought to be important for neuroprotective inflammatory responses. Activated astrocytes exhibit upregulation of inflammatory genes in both familial and sporadic ALS and acquire neurotoxicities by reduction of glutamate uptake or production of unknown toxic factors. Astrocytes also have an important role in regulating neuroinflammation of ALS by interfering with the beneficial effects of neuroinflammation partly by production of transforming growth factor–β1. Many clinical trials for ALS targeting neuroinflammation, together with a further understanding of the role of neuroinflammation in disease, will lead to the development of novel therapeutics for ALS.

Both TAR DNA binding protein of 43kDa (TDP–43) pathology and failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2, a subunit of the α–amino–3–hydroxy–5–methyl–4–isoxazole propionic acid (AMPA) receptor, are the characteristic etiology–linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS), the most common adult–onset fatal motor neuron disease. Adenosine deaminase acting on RNA 2 (ADAR2) specifically catalyzes RNA editing at the Q/R site of GluA2, and conditional ADAR2 knockout mice (ADAR2^flox/flox/VAChT–Cre.Fast ; AR2 mice) exhibit a progressive ALS phenotype with TDP–43 pathology–like TDP–43 mislocalization in the ADAR2–lacking motor neurons. Because Ca²⁺–permeable AMPA receptor–mediated mechanism underlies death of motor neurons in the AR2 mice, amelioration of exaggerated Ca²⁺ influx by AMPA receptor antagonists may be a potential ALS therapy. Here we showed that oral perampanel, a selective non–competitive AMPA receptor antagonist, significantly prevented progression of ALS phenotype and death of motor neurons with effective normalization of TDP–43 pathology in the AR2 mice. Given that perampanel has already been approved as an anti–epileptic drug, perampanel would be a potential candidate ALS drug.

Amyotrophic Lateral Sclerosis (ALS) is a devastating disease characterized by the progressive loss of motor neurons. A number of genes involved in the etiopathology of ALS have been identified, and studies in vivo and in vitro models have clarified the contribution of several genetic and physiological abnormalities to the disease onset and progression.

However, a complete understanding of the ALS molecular mechanisms has yet to be determined. In addition, no cure or effective treatment have been found for ALS.

In the 2006, in vitro technologies to model neurological disorders have undergone impressive developments. The development of induced pluripotent stem cells (iPSCs) enable researchers to make the patient–derived ALS model in vitro, which can reproduce the whole ALS pathology in a dish from onset to death. These iPSC–derived ALS models can also be a powerful and versatile tool for finding ALS therapeutic agents as well as basic research of ALS pathology.

Here, we will discuss the efforts so far to create iPSC–dependent, ALS patient–specific disease models. Furthermore, we will give an overview of how human iPSC–based in vitro models have been established and used, what discoveries they have led to, what outcomes they have returned to society/ALS–patient, and how the recent advances in iPSC technology would expand the field of ALS study.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is an adult–onset neuromuscular disease caused by an expansion of a CAG triplet–repeat within the first exon of the androgen receptor gene. Recent studies have indicated that SBMA is not a pure neurodegenerative disease, but affecting various non–neuronal tissues, including skeletal muscle. Furthermore, impairment in the interaction between motor neurons and skeletal muscles may be the key mechanism underlying the pathophysiology of SBMA. In the presence of testosterone, a disease–causing abnormal AR protein accumulates in the brainstem, spinal anterior horn, skeletal muscle, and several peripheral organs ; this induces a variety of symptoms, such as bulbar and muscular atrophy, liver dysfunction, and arrhythmia, in patients with SBMA. Studies using animal models have resulted in the development of promising therapeutic strategies for SBMA, including 1) testosterone suppression, 2) mutant androgen receptor gene silencing, 3) activation of protein quality control, and 4) rescuing of mitochondrial function. Efficacy of physical therapy has also been tested in small–scale clinical trials. In this review, we describe the clinical features and pathogenesis of SBMA, and summarize the therapeutic drug targets developed on the basis of results from recent studies using the well–established mouse models for this neuromuscular disease. Strategies for the development of disease–modifying therapy supported by basic experiments as well as well–planned clinical trials may lead to a breakthrough in the therapy for SBMA.

Asidan, which is a nicknamed of spinocerebellar ataxia type 36 (SCA36), is a novel dominant disorder caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene. Common symptoms of Asidan patients are truncal ataxia, dysarthria and limb ataxia (a sign of cerebellar ataxia), hyperreflexia and tongue atrophy, fasciculation (a sign of motor neuron disease), cognitive and affective impairment and hearing loss. Therefore, Asidan stands at the crossroads of SCA and motor neuron disease. (GGCCUG)n repeat RNA foci formation was detected in lymphoblastoid cells from Asidan patients by fluorescence in situ hybridization. Double staining and gel–shift assay showed that (GGCCUG)n binds the RNA–binding protein SRSF2, suggesting that Asidan is caused by hexanucleotide repeat expansions through RNA gain of function. Interestingly, G93A–SOD1 transgenic mice, which is a ALS model mouse, show progressive reduction of NOP56 levels in the large motor neurons of spinal cords from the early–symptomatic stage to the end stage of the disease. TDP–43 and FUS protein levels, which participates in RNA processing pathway similar to NOP56, showed a later decrease in the nucleus of large motor neuron at end stage of the disease. These changes were not observed in the primary motor cortex of the cerebrum as well as molecular and granular layers and Purkinje cells in the cerebellum, suggesting a progressive loss of these three nuclear proteins, especially NOP56, and subsequent RNA processing problems including a novel gene relating to ALS (NOP56) under the motor neuron degeneration. Recent reports showed sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population is caused by hexanucleotide GGGGCC repeat expansion in intron 1 of the C9orf72 gene, similar to the genetic mutation in Asidan patients. Since C9orf72 mutation induces neurodegeneration of Purkinje cells, it is possible that a similar genetic pathology for cerebellar ataxia, motor neuron disease signs and cognitive impairment may be at play in both Asidan and ALS/FTD.

Purpose : Difficulty in taking medications results in inaccurate judgments regarding the effects of treatment with oral medication and impairs medication adherence. We investigated the present situation with regard to difficulty in taking medications for patients with neurological diseases.

Methods : Difficulty in taking medication was defined as cases in which a patient experienced difficulty swallowing or had to swallow three or more times, had to wash the medication down with water or jelly, choked on drugs, had drug residue or a feeling of residue in the oral cavity, pharynx, or esophagus, or coughed up drugs, or had drug residue around the mouth. We examined patients ≥65 years old with neurological diseases from 26 facilities who were deemed to have difficulty taking medication by a medical professional specializing in dysphagia. As adhesion experiment of drug to review the association of drug residue and pharmaceutical adherence, a total of 0.3ml of water was dropped onto the drug placed on a cellulose acetate film sheet.

Results : This study identified 136 patients with difficulties taking medication. Medication was self–administered in 27% of patients, regular meals of a non–modified diet were consumed by 34% of patients, and swallowing screening tests yielded normal results in 33% of patients. Drug residue was seen in the oral cavity or pharynx in any dosage form in 55% of patients. In adhesion experiments, water was dropped on to five dosage forms of drugs, sugar–coated tablets have the lowest adhesiveness, strong adhesion with film tablet, orally disintegrating tablets, film–coated tablets, and uncoated tablets. In seven types of generic orally disintegrating tablets having the same effect, adhesiveness and disintegration varies depending on the drug.

Conclusions : Medication difficulties appear to occur regardless of medication independence, regular meal texture, results of swallowing screening tests or the dosage form. Clinical observation and cooperation by medical staff responsible for medication management are therefore necessary.

High–flow nasal cannula (HFNC) oxygen therapy is a method of respiratory care using a novel oxygen–supplying device. This therapy is rapidly becoming widespread due to the high efficacy of oxygenation and preservation of patient quality of life. An 87–year–old woman developed CO₂ narcosis from aspiration pneumonia and atelectasis 2 days after lateral medullary infarction. Because the family did not want tracheal intubation, and because non–invasive positive pressure ventilation (NPPV) was withheld due to the requirement for frequent suction, the patient was treated with HFNC oxygen therapy. Arterial blood gas analysis revealed improvement of hypercapnia 1h after applying HFNC oxygen therapy. The patient recovered consciousness after 6h of HFNC oxygen therapy. HFNC was switched to routine oxygenation after a week. No progression of medullary infarction was detected during the course, and the patient was transferred to a rehabilitation facility. HFNC oxygen therapy has advantages in bronchial drainage, although tracheal intubation or NPPV should first be applied for respiratory failure with hypercapnia. HFNC oxygen therapy represents a useful option for clinicians with sufficient knowledge about its merits and demerits, when mechanical ventilation must be withheld considering the background of the patient.

We evaluated 5 ALS patients without positive–pressure mechanical ventilation who utilized diaphragm pacing (DP) with NeuRx Diaphragm Pacing System (NeuRx DPS^®) with 24 months of follow–up. Several anticipated non–serious adverse events, such as discomfort and pain with pacing (5 patients), break of external cable (3 patients), and focal skin infection (2 patients) occurred, however, we observed no sequelae or interruption of pacing. During the follow–up period, 2 patients without bi–level positive airway pressure (BIPAP) died from aspiration pneumonia or chronic respiratory failure. 1 of 3 patients with BIPAP was introduced mechanical ventilation because of aspiration. However, other 2 patients needed neither tracheotomy nor positive–pressure mechanical ventilation during the observation period. Clinical efficacy of NeuRx DPS^® for ALS has not been elucidated yet. Further investigation for proper indication and pacing condition of NeuRx DPS^® is necessary.

A 59–year–old woman suffering from amyotrophic lateral sclerosis with non–invasive positive pressure ventilation (NPPV) therapy at night was in home care. She strongly desired to travel by air. We confirmed the following : (1) The NPPV device does not operate normally on board because there is no pressure correction function. (2) An oxygen cylinder specified by the airline can be used. (3) There is a protocol for bringing the equipment into the plane. In case of an emergency, we taught her family the ventilation procedures using a bag valve mask. We prepared a letter for emergency consultation during the travel and stayed in contact with ventilator dealers at the travel destination in order to respond in case of an emergency. The travel was completed without trouble. Thus, it is possible to travel by air with the NPPV device under appropriate medical support.