Kazuaki Nagashima

Melanophilin directly links Rab27a and myosin Va through its distinct coiled-coil regions

Rab GTPases regulate the membrane transport pathways by recruiting their specific effector proteins. Melanophilin, a putative Rab effector, has recently been identified as a gene that is mutated in leaden mice, in which peripheral localization of melanosomes is impaired in melanocytes. Genetic studies suggest that three coat‐color mutation genes, dilute (MyoVad ), ashen (Rab27aash ), and leaden (Mlphln ), act in the same or overlapping pathways. Here we have cloned and characterized a human melanophilin homolog, which belongs to the rabphilin3/granuphilin‐like Rab effector family. Cosedimentation assays using recombinant proteins reveal that melanophilin directly binds to Rab27a and myosin Va through its N‐terminal and its first C‐terminal coiled‐coil region, respectively. Moreover, we show that Rab27a, melanophilin, and myosin Va form a ternary complex in the human melanocyte cell line HMV‐II. These findings suggest that melanophilin has a role in bridging Rab27a on melanosomes and myosin Va on actin filaments during melanosome transport. We also propose that the Rab‐binding region conserved in a novel rabphilin3/granuphilin‐like Rab effector family constitutes an α‐helix‐based coiled‐coil structure.

Neuropathological study of C57BL/6Akita mouse, type 2 diabetic model : Enhanced expression of αB-crystallin in oligodendrocytes

The structure of the central and peripheral nervous systems was studied in the C57BL/6Akita (Akita) mouse, a non‐obese type 2 diabetes model characterized by early onset, autosomal dominant inheritance and a mutation of the insulin 2 gene. Usual neuropathological examinations showed no remarkable abnormalities in the brain, spinal cord or sciatic nerve of Akita mice up to 48 weeks of age. However, immunohistochemical examination revealed that expression of αB‐crystallin was enhanced in oligodendrocytes in the cerebral white matter, especially in the corpus callosum, after 32 weeks of age. The oligodendrocytes were not positive for ubiquitin and HSP25. It is suggested that long‐standing hyperglycemia might stress the CNS and thus enhance the expression of αB‐crystallin in oligodendrocytes.

An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis

A percutaneous endoscopic gastrostomy (PEG) is an useful intervention for feeding of amyotrophic lateral sclerosis (ALS) patients who have lost oral intake function. The aim of this study was to investigate the risk factors for early death and the survival after PEG placement. A total of 102 ALS patients who underwent PEG placement were enrolled in this study. Patients were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics, respiratory function, and nutritional parameters were compared for the two groups to assess the correlations between clinical and laboratory variables and early death after PEG placement. Multivariate analysis between two groups revealed that higher arterial carbon dioxide pressure (PaCO2) and aphagia before PEG placement were significantly associated with the poor prognosis group. Multivariate analysis for survival also revealed that higher PaCO2 and shorter duration from onset to PEG placement were significantly associated with shorter survival after PEG placement. In conclusion, respiratory and nutritional parameters are revealed to be important prognostic factors for ALS patients who undergo PEG placement.

Charcot-Marie-Tooth disease showing transient central nervous system lesions after a large amount of alcohol intake: A case report

A 23-year-old man experienced numbness in the perioral region and right arm, and right leg weakness on the second day after drinking a large amount of alcohol during foreign travel. His symptoms disappeared but then reappeared repetitively. Cerebral MRI performed on the third day after onset showed multiple white matter lesions; however, these lesions disappeared 26 days after onset. Neurological examination and nerve conduction studies revealed demyelinating polyneuropathy. Genetic testing for Charcot-Marie-Tooth disease, X-linked dominant 1 (CMTX1) due to GJB1 mutation was conducted based on the symptoms of transient central nervous system lesions and polyneuropathy exhibited by the patient and his mother. As a result, a c.530T>C (p.V177A) substitution in exon 2 of GJB1 was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.

Putaminal iron deposition precedes MSA-P onset by 2 years

Changes in putaminal MRI signals are important imaging biomarkers for the diagnosis of multiple system atrophy with predominant parkinsonism (MSA-P). However, there exists little data on the first occurrence of these changes in the natural history of the disorder.

Tumoral ectopic calcinosis causing cervical spinal cord compression in a patient with systemic sclerosis

A 54 year-old woman complained of neck pain, weakness and dysesthesia of the upper limbs. She had had a medical history of systemic sclerosis diagnosed at 52 years old. Neurological examination revealed bilateral biceps reflexes are normal, however, bilateral triceps, patellar, and Achilles’ tendon reflexes were hyperactive. Cervical spinal MRI showed a tumoral lesion located in the posterior part of the spinal canal at the levels of C3-5 (Figs. 1a and 1b), and its internal portion was not clearly enhanced with gadolinium (Fig. 1c). This lesion entirely showed high density on CT (Fig. 1d), and was considered to be generated from an ectopic calcinosis due to systemic sclerosis. Macroscopic findings during surgery identified the ectopic calcinosis existed in the epidural space with intact dura mater. Pathological evaluation after the total resection (Fig. 1e) revealed it was actually a soft calcified tissue. After the surgical resection, her clinical symptoms were remarkably improved. It should be noticed that a tumoral ectopic calcinosis occurred in the spinal canal can rarely cause myelopathy or myeloradiculopathy in a patient with systemic sclerosis.1 This article is protected by copyright. All rights reserved.

MICROBLEEDS IN CLINICAL SUBTYPES OF ALZHEIMER'S DISEASE ON CSF AND NEUROIMAGING MARKERS

(BMI) is associated with reduced risk for future development of Alzheimer’s Diseases (AD), particularly in older subjects (Emmerzaal et al., 2015). Therefore, we sought to investigate how BMI in late middle aged and elderly subjects relates to regional cerebral metabolic rate of glucose (rCMRgl) and whether this relationship is influenced by the status of APOEε4 allele, a genetic risk for AD, or age. Methods: 197 cognitively healthy, non-diabetic subjects (59M/138F; age 61.066.3y; BMI 27.364.9kg*m), including homozygous (n1⁄440) and heterozygous (n1⁄458) carriers of the APOEε4 allele, underwent quantification of rCMRgl using 2-[F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography. Voxelwise multiple regression analyses across the whole brain and within specific regions of interest (ROI) including precuneus, posterior cingulate, parietal, temporal, prefrontal, and occipital brain regions were employed to investigate associations of BMI with rCMRgl and potential interactions with APOEε4 carrier status, age and gender. Furthermore, we applied the hypometabolic convergence index (HCI; Chen et al., 2011) in order to explore the relationship between BMI and AD typical hypometabolic patterns. Results:We found extensive and exclusively positive associations of BMI with rCMRgl in regions known to be affected by AD such as occipital, parietal, temporal (including the bilateral hippocampal region), and other brain regions (i.e. cerebellum, frontoinsular and subcortical regions). Confirmatory results were found for specific ROIs. A significant BMI by gender interaction was observed with stronger associations within the right temporal and the right orbitofrontal cortex in males. However, no significant BMI by APOEε4 carrier status interaction or BMI by age group interaction was detected. Additionally, BMI was negatively correlated with HCI, indicating less convergence to AD typical hypometabolic patterns in subjects with high BMI measures. Conclusions: BMI is positively associated with rCMRgl in healthy late middle aged and elderly subjects, including brain regions that are typically affected by AD, thus providing a potential explanation for the proposed beneficial effects of higher BMI with respect to AD development. These associations seem to be modified by gender, possibly as the result of differences in body composition, but not by APOEε4 genotype or age.