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Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importinβ1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired. Abbreviations: ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementiaC9ALS-FTD, C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal dementiaCS, citrate synthaseER, endoplasmic reticulumGSS, glutathione synthetaseHRE, hexanucleotide repeat expansionHSPA5/BiP, heat shock protein 5LAMP1, lysosomal-associated membrane protein 1MAM, mitochondria-associated endoplasmic reticulum membraneMAP1LC3/LC3, microtubule-associated protein 1 light chain 3NP, nuclear poreNSC34, mouse motor neuron-like hybrid cell lineNUPs, nucleoporinsPOM121, nuclear pore membrane protein 121SIGMAR1/Sigma-1R, sigma non-opioid intracellular receptor 1TFEB, transcription factor EBTMEM97/Sigma-2R, transmembrane protein 97 [ABSTRACT FROM AUTHOR]

Objectives: Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. Aim: This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. Methods: Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and high-cholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks. Results: The HFC diet significantly increased serum transaminase and gamma glutamyl transpeptidase activities, tumor necrosis factor alpha levels, and serum and hepatic total cholesterol levels over time. In contrast, this diet decreased serum albumin, glucose, and adiponectin levels throughout or the later stage of the feeding period, but did not influence serum insulin levels. Histopathologically, the HFC diet increased microvesicular steatosis, and focal or spotty necrosis with lymphocyte infiltrations were observed in the liver at 2 weeks, macrovesicular steatosis, ballooned hepatocytes with Mallory-Denk body formation in some, and multilobular necrosis and fibrosis at 8 weeks. Interestingly, this fibrosis formed a honeycomb network at 14 weeks. These changes are very similar to those observed in patients with non-alcoholic steatohepatitis. Conclusions: SHRSP5/Dmcr rats appear to be a useful model for analyzing the time-dependent changes of HFC diet-induced steatohepatitis and fibrosis progression. [ABSTRACT FROM AUTHOR]

Objectives: The study was conducted to analyze risk, causes and places of death, and related factors among elderly with and without dementia in a community., Methods: In 1994, the entire elderly population, aged 65 and older in city K were surveyed for their health status. Among them, 201 were diagnosed as suffering from dementia by psychiatric doctors, according to DSM-III-R. Date, causes and places of death were surveyed individually using the vital statistics record of the national government, for ten years from July 1, 1994. The risk of death adjusted for age-classes, was analyzed with the Cox proportional hazard model. Median survival time was calculated using the Kaplan-Maier method, and causes and places of death were analyzed with the chi2 test. Ten factors at the baseline study were examined for each sex, to analyze their relations to death., Results: Among 198 elderly with dementia followed, 170 died (85.9%), while 1696 (33.9%) died in the 5004 non-dementia group. The hazard ratio for dementia/non-dementia was 2.99, and the female/male was 0.56, stratified by age-classes. The rate for death due to CVD in the elderly with dementia was particularly high accounting for 37.1% of the total. With the CVD and undifferentiated types of dementia, the rate was 47.0%. The rate for malignant tumor was low. In the dementia group, mortality at nursing homes was higher and at hospitals/clinics was lower, compared to non-dementia group (p< 0.05). When stratified by age-classes, the factors significantly related to death of the elderly with dementia were severity of dementia (male), type of dementia (female), being bed-ridden and having impaired walking or toileting capabilities (both sexes)., Conclusions: Dementia is a significant death related factor for elderly people, particularly linked to mortality from cerebro-vascular disease. The type and severity of dementia, and walking or toileting activities appear significant to be factors for death of elderly with dementia.