Loss-of-function mutations in the mouse ortholog of C9ORF72 cause fatal autoimmunity that is transferable by bone marrow–derived cells, demonstrating a hematopoietic intrinsic function for the protein encoded by this gene.

Forkhead box O (Foxo) transcription factors induce muscle atrophy by upregulating the muscle-specific E3 ubiquitin ligases MuRF-1 and atrogin-1/MAFbx, but other than Akt, the upstream regulators of Foxos during muscle atrophy are largely unknown. To examine the involvement of the dystrophin glycoprotein complex (DGC) in regulation of Foxo activities and muscle atrophy, we analyzed the expression of DGC members during tail suspension, a model of unloading-induced muscle atrophy. Among several DGC members, only neuronal NOS (nNOS) quickly dislocated from the sarcolemma to the cytoplasm during tail suspension. Electron paramagnetic resonance spectrometry revealed production of NO in atrophying muscle. nNOS-null mice showed much milder muscle atrophy after tail suspension than did wild-type mice. Importantly, nuclear accumulation of dephosphorylated Foxo3a was not evident in nNOS-null muscle, and neither MuRF-1 nor atrogin-1/MAFbx were upregulated during tail suspension. Furthermore, an nNOS-specific inhibitor, 7-nitroindazole, significantly prevented suspension-induced muscle atrophy. The NF-κB pathway was activated in both wild-type and nNOS-null muscle during tail suspension. We also show that nNOS was involved in the mechanism of denervation-induced atrophy. We conclude that nNOS/NO mediates muscle atrophy via regulation of Foxo transcription factors and is a new therapeutic target for disuse-induced muscle atrophy.

Skeletal muscle is one of the most abundant and highly plastic tissues. The ubiquitin–proteasome system (UPS) is recognised as a major intracellular protein degradation system, and its function is important for muscle homeostasis and health. Although UPS plays an essential role in protein degradation during muscle atrophy, leading to the loss of muscle mass and strength, its deficit negatively impacts muscle homeostasis and leads to the occurrence of several pathological phenotypes. A growing number of studies have linked UPS impairment not only to matured muscle fibre degeneration and weakness, but also to muscle stem cells and deficiency in regeneration. Emerging evidence suggests possible links between abnormal UPS regulation and several types of muscle diseases. Therefore, understanding of the role of UPS in skeletal muscle may provide novel therapeutic insights to counteract muscle wasting, and various muscle diseases. In this review, we focussed on the role of proteasomes in skeletal muscle and its regeneration, including a brief explanation of the structure of proteasomes. In addition, we summarised the recent findings on several diseases and elaborated on how the UPS is related to their pathological states.

Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing onSOD1, fused in sarcoma(FUS), and transacting response DNA-binding protein. The frequency of theC9ORF72mutation is low in Japan, unlike in Europe and the United States, whileSOD1andFUSare more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extended transverse myelitis (LETM). The clinical and laboratory features of NMO are different from multiple sclerosis (MS).1 An autoantibody to aquaporin-4 (AQP4) has been detected exclusively in the NMO sera.1 Moreover, we demonstrated an extensive loss of AQP4 and glial fibrillary acidic protein immunoreactivities in the perivascular regions with complement and immunoglobulin deposition in NMO that suggests astrocytic impairment. However, when AQP4 antibody is produced in patients with NMO is unknown, and thus it remains unresolved whether there are long-term asymptomatic AQP4 antibody–positive carriers, whether AQP4 antibody alone can be pathogenic, and whether AQP4 antibody is produced secondarily as a result of tissue destruction in attacks of NMO. We herein report a case of NMO in which AQP4 antibody was detected years before the NMO onset. ### Case report. A 34-year-old healthy woman without previous history of inflammatory or neurologic diseases noticed temporary skin eruptions on her chest and shoulders in June 2007. A dermatologist made the diagnosis of eczema. Three weeks later, when the skin eruptions subsided, she noted progressive paresthesia in the chest and toes. Within a few days, she could not walk well due to right leg weakness, and then she was hospitalized. Neurologic examination on …