Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.

Transnasal EGD is safer than transoral EGD as it is associated with fewer adverse effects on cardiopulmonary function and is better tolerated by patients.

The nucleocytoplasmic transport system is essential for maintaining cell viability; transport of proteins and nucleic acids between the nucleus and the cytoplasm occurs through nuclear pore complexes (NPCs). In this study, we examined the immunohistochemical distribution of the major protein components of NPCs, Nup62, Nup88, and Nup153, in spinal cords from controls and patients with sporadic or familial amyotrophic lateral sclerosis (SALS or FALS) and its mouse model. In control subjects, immunolabeling on the nuclear envelopes of anterior horn cells (AHCs) was invariably smooth and continuous, whereas in SALS and FALS patients, the AHCs predominantly showed irregular nuclear contours. Double immunofluorescence staining demonstrated that in SALS patients, importin-beta immunoreactivity was absent in the nuclei in a subset of AHCs; in these cells, Nup62 immunolabeling of nuclear membrane was invariably irregular, suggesting that there was dysfunctional nucleocytoplasmic transport in those AHCs. In the mouse model, Nup62-immunolabeled AHCs with irregular nuclear contours were predominant as early as the presymptomatic stage and the contours became progressively discontinuous along with disease development. Together, these observations suggest that dysfunctional nucleocytoplasmic transport may underlie the pathogenesis of ALS.

This report concerns an immunohistochemical investigation on RNA-related proteins in the basophilic inclusions (BIs) from patients with adult-onset atypical motor neuron disease. Formalin-fixed, paraffin-embedded sections of the motor cortex and the lumbar spinal cord were examined. The BIs appeared blue in color with H&E and Nissl stain, and pink with methylgreen-pyronin stain. Ribonuclease pretreatment abolished the methylgreen-pyronin staining, suggesting that the BIs contained RNA. Immunohistochemically, the BIs were distinctly labeled with the antibodies against poly(A)-binding protein 1, T cell intracellular antigen 1, and ribosomal protein S6. These proteins are essential constituents of stress granules. In contrast, the BIs were not immunoreactive for ribosomal protein L28 and decapping enzyme 1, which are core components of transport ribonucleoprotein particles and processing bodies, respectively. Moreover, the BIs were not immunopositive for TDP-43. Our results imply that translation attenuation could be involved in the processes of BI formation in this disorder.

In transnasal small-caliber EGD, oolong tea instead of water as a washing solution for endoscopic lens cleansing is useful to maintain good visibility.