RESUMO
Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope (env) gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK env transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Animais , Conotoxinas/genética , Conotoxinas/metabolismo , Retrovirus Endógenos/metabolismo , Retrovirus Endógenos/patogenicidade , Humanos , NF-kappa B/metabolismo , Necroptose/genética , Necroptose/fisiologia , Retroviridae/genética , Retroviridae/patogenicidadeRESUMO
Energy projects may profoundly impact Indigenous peoples. We consider effects of Canada's proposed Trans Mountain oil pipeline expansion on the health and food sovereignty of the Tsleil-Waututh Nation (TWN) through contamination and impeded access to uncontaminated traditional foods. Federal monitoring and TWN documentation show elevated shellfish biotoxin levels in TWN's traditional territory near the terminus where crude oil is piped. Although TWN restoration work has re-opened some shellfish-harvesting sites, pipeline expansion stands to increase health risk directly through rising bioaccumulating chemical toxins as well as through increased hazardous biotoxins. Climate change from increased fossil fuel use, expected via pipeline expansion, also threatens to increase algae blooms through higher temperature and nutrient loading. As the environmental impact assessment process failed to effectively consider these local health concerns in addition to larger impacts of climate change, new assessment is needed attending to linked issues of equity, sustainability and Indigenous food sovereignty.
Assuntos
Exposição Ambiental/efeitos adversos , Abastecimento de Alimentos , Equidade em Saúde , Povos Indígenas , Campos de Petróleo e Gás , Petróleo , Animais , Canadá , Mudança Climática , Proliferação Nociva de Algas , Humanos , Frutos do Mar/toxicidadeRESUMO
OBJECTIVE: Upregulation of uncoupling protein 2 (UCP2) is associated with impaired glucose-stimulated insulin secretion (GSIS), which is thought to be an important contributor to pathological ß cell failure in obesity and type 2 diabetes (T2D); however, the physiological function of UCP2 in the ß cell remains undefined. It has been suggested, but not yet tested, that UCP2 plays a physiological role in ß cells by coordinating insulin secretion capacity with anticipated fluctuating nutrient supply, such that upregulation of UCP2 in the inactive/fasted state inhibits GSIS as a mechanism to prevent hypoglycemia. Therefore, we hypothesized that daily cycles of GSIS capacity are dependent on rhythmic and predictable patterns of Ucp2 gene expression such that low Ucp2 in the active/fed phase promotes maximal GSIS capacity, whereas elevated Ucp2 expression in the inactive/fasted phase supresses GSIS capacity. We further hypothesized that rhythmic Ucp2 expression is required for the maintenance of glucose tolerance over the 24 h cycle. METHODS: We used synchronized MIN6 clonal ß cells and isolated mouse islets from wild type (C57BL6) and mice with ß cell knockout of Ucp2 (Ucp2-ßKO; and respective Ins2-cre controls) to determine the endogenous expression pattern of Ucp2 over 24 h and its impact on GSIS capacity and glucose tolerance over 24 h. RESULTS: A dynamic pattern of Ucp2 mRNA expression was observed in synchronized MIN6 cells, which showed a reciprocal relationship with GSIS capacity in a time-of-day-specific manner. GSIS capacity was suppressed in islets isolated from wild type and control mice during the light/inactive phase of the daily cycle; a suppression that was dependent on Ucp2 in the ß cell and was lost in islets isolated from Ucp2-ßKO mice or wild type islets treated with a UCP2 inhibitor. Finally, suppression of GSIS capacity by UCP2 in the light phase was required for the maintenance of normal patterns of glucose tolerance. CONCLUSIONS: Our study suggests that Ucp2/UCP2 in the ß cell is part of an important, endogenous, metabolic regulator that controls the temporal capacity of GSIS over the course of the day/night cycle, which, in turn, regulates time-of-day glucose tolerance. Targeting Ucp2/UCP2 as a therapeutic in type 2 diabetes or any other metabolic condition must take into account the rhythmic nature of its expression and its impact on glucose tolerance over 24 h, specifically during the inactive/fasted phase.
Assuntos
Ritmo Circadiano , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proteína Desacopladora 2/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Exocitose , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Desacopladora 2/genéticaRESUMO
The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the "S-allele" present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting ß cells. Few studies on the impact of the HNF-1αG319S variant on ß cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in ß cell glucose-sensing, mitochondrial function, and the maintenance of the ß cell phenotype in differentiated ß cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the ß cell to better inform future research into the mechanisms of ß cell dysfunction in Oji-Cree youth with T2D.