Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases.

The endoplasmic reticulum, a key cellular organelle, regulates a wide variety of cellular activities. Endoplasmic reticulum autophagy, one of the quality control systems of the endoplasmic reticulum, plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover, remodeling, and proteostasis. In this review, we briefly describe the endoplasmic reticulum quality control system, and subsequently focus on the role of endoplasmic reticulum autophagy, emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements. We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases. In summary, this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders. This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription.

Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully understood. Voltage-gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD-related abnormal neuronal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we have shown that the reduction of VGSC α-subunit Nav1.6 (by injecting adeno-associated virus (AAV) with short hairpin RNA (shRNA) into the hippocampus) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 transgenic mice. Concurrently, amyloid plaques in the hippocampus and levels of soluble Aß are significantly reduced. Interfering with Nav1.6 reduces the transcription level of ß-site APP-cleaving enzyme 1 (BACE1), which is Aß-dependent. In the presence of Aß oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium-calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aß in APP/PS1 transgenic mice, alleviates synaptic loss, improves learning and memory disorders in APP/PS1 mice after downregulating Nav1.6 in the hippocampus. Our study offers a new potential therapeutic strategy to counteract hippocampal hyperexcitability and subsequently rescue cognitive deficits in AD by selective blockade of Nav1.6 overexpression and/or hyperactivity.

Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.

Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.

Responses of Han migrants compared to Tibetans at high altitude.

While many studies have compared Tibetans and low-altitude born Han living at high altitude, few have carefully controlled the chronological age at which lowlanders migrated, the length of time they had lived at high altitude, their nutrition, and their socio-economic status. This has produced an array of results that frequently do not support the hypothesis that Tibetans and Han show fundamental differences in their response to hypoxia. Unlike the situation in the Andes, only one study has tested the developmental adaptation hypothesis on the Qinghai-Tibetan plateau. This study shows that Tibetans and Han of the same age, who were born and raised in the same towns at the same altitudes, show considerable overlap in the individual distribution of [Hb], SaO2 and lung volumes. These results indicate that second-generation Han make substantial developmental adjustments to hypoxia that are not reflected in studies of first-generation migrants. Thus, there is a great need for further developmental studies to determine whether and/or how Han and Tibetan responses to hypoxia diverge, as well as for studies exploring whether Han and Tibetans who show similar responses also share genetic adaptations.

Morphological growth and thorax dimensions among Tibetan compared to Han children, adolescents and young adults born and raised at high altitude.

BACKGROUND: Studies comparing the growth of indigenous high-altitude Aymara children and children of low-altitude European descent who have been born and raised at high altitude in the Andes have provided evidence for genetically-determined differences in thorax growth, as well as for population differences in height, weight and other measures of overall size. Comparable studies now can be undertaken in Asia because of the growing number of Han Chinese who have been born and raised at high altitude on the Qinghai-Tibetan Plateau. AIM: The study compares the growth of indigenous Tibetan children and children of Han descent who have been born and raised at the same high altitudes, and under similar socio-economic conditions. SUBJECTS AND METHODS: Measurements of stature, sitting height, weight, triceps and subscapular skinfolds, upper arm muscle area, transverse chest diameter, anterio-posterior chest diameter, and chest circumference were taken on 1439 Tibetan and Han males and females between the ages of 6 and 29 years who were born and raised 3200 m, 3800 m or at 4300 m in the high altitude province of Qinghai in western China. RESULTS: Han-Tibetan differences in body size do not occur systematically for any measurement, for any age group, or for either gender; nor is there a systematic pattern of body size differences between 3200 m and 4300 m. This indicates that there are no differences in general growth between the two groups at high altitude in Qinghai, although both groups grow more slowly than urban children at low altitude in China. On the other hand, Tibetan males possess significantly deeper chests than Han males, and Tibetan females possess significantly wider chests than Han females. Tibetans of both sexes possess significantly larger chest circumferences than Han males and females. CONCLUSIONS: Although genetic similarities cannot be ruled out, comparable dietary stress is a likely explanation for the similar and slow morphological growth of Han and Tibetans at high altitude. However, Han-Tibetan differences in thorax dimensions are likely a consequence of population (genetic) differences in the response to hypoxia during growth.

Hematological differences during growth among Tibetans and Han Chinese born and raised at high altitude in Qinghai, China.

This study describes the hemoglobin concentration ([Hb]) and hematocrit (HCT) of over 1,000 Tibetan and Han children, adolescents, and young adults who were born and raised at 3,200 m, 3,800 m, or 4,300 m in Qinghai Province, western China. At 3,200 m, no altitude effect is evident in the hematological characteristics of either group. At 3,800 m and 4,300 m, both groups show [Hb] and HCT values that are above low-altitude norms. At both altitudes, Tibetan and Han children show no differences in the pattern of hematological response up to age 13. Among adolescents and young adults, however, the [Hb] and HCT of Han males and females are elevated compared to Tibetans. This indicates that the adolescent period may involve a divergence in the responses to hypoxia made by some individuals in these two groups. Also, many other adolescents and young adults in both groups show similar hematological characteristics, indicating that many Tibetans and Han share similar hematological responses to hypoxia.

Lung function of Han Chinese born and raised near sea level and at high altitude in Western China.

Forced vital capacity (FVC), forced expiratory volume at 1 second (FEV(1)), and FEV(1)/FVC ratios were determined for 531 individuals of Han Chinese descent living at low altitude (250 m) near Beijing and for 592 individuals of Han descent who were born and raised at three high altitudes (3,200 m, 3,800 m, 4,300 m) in Qinghai Province, P.R.C. The study included males and females, ages 6-51 years. Thorax widths, depths, and circumferences of Han females and males born and raised at high altitude are similar to those of low-altitude Han. On the other hand, high-altitude children and adolescents have larger relative sitting heights, indicating greater thorax lengths. After adjusting for this variation in morphology, mean FVC values among 6-21 year-old Han at high altitude are only between 136 mL (for females) and 173 ml (for males) greater than those determined at low altitude but the differences are statistically significant and are maintained consistently throughout the growth period. These data indicate that growth at high altitude produces small-to-moderate increases in lung volumes (about 6%) relative to genetically similar groups growing up at low altitude. In addition, there is no evidence that lung volume growth is accelerated relative to morphological growth among Han children born and raised at high altitude. Adults, 22-51 years, also show greater FVC values at high altitude but the size of the increase relative to Han at low altitude is variable (3% in males and 11% in females). Greater lung function at high altitude is unlikely to result from increased activity or lower pollution, and thus appears to be primarily a result of development in a hypoxic environment. Differences in FVC and FEV(1) at 3,200 m, 3,800 m, and 4,300 m are generally not significant, so that living at altitudes between 3,200 m and 4,300 m appears to have little additional effect on volumetric growth.

Morphological growth of Han boys and girls born and raised near sea level and at high altitude in western China.

This study compares the morphological characteristics of Han children, adolescents, and young adults who were born at 250 m near Beijing and at three high altitudes in Qinghai Province, Peoples Republic of China (3,200 m, 3,800 m, and 4,300 m). From ages 6 through 15, Han children growing up at high altitudes are significantly shorter, lighter, have less fat, and are less muscular than Han children growing up at low altitude. However, older adolescents and young adults show no such altitude differences. Younger adolescents and children in this study were all born after the government economic reforms of 1978. These reforms had a greater impact on the growth of children in and around large cities than on those in more remote areas. Therefore, the altitude differences in size among Han children ages 15 and younger may be a consequence of regional variation in health and nutrition, rather than due to the influence of hypoxia. There are no altitude-related differences in thorax dimensions among Han children, adolescents, or young adults. This suggests that hypoxia does not affect the thorax growth of Han children. Am. J. Hum. Biol. 12:665-681, 2000. Copyright 2000 Wiley-Liss, Inc.