Modestly increased expression of transactive response DNA binding protein (TDP-43) gene have been reported in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neuromuscular diseases. However, whether this modest elevation triggers neurodegeneration is not known. Although high levels of TDP-43 overexpression have been modeled in mice and shown to cause early death, models with low-level overexpression that mimic the human condition have not been established. In this study, transgenic mice overexpressing wild type TDP-43 at less than 60% above the endogenous CNS levels were constructed, and their phenotypes analyzed by a variety of techniques, including biochemical, molecular, histological, behavioral techniques and electromyography. The TDP-43 transgene was expressed in neurons, astrocytes, and oligodendrocytes in the cortex and predominantly in astrocytes and oligodendrocytes in the spinal cord. The mice developed a reproducible progressive weakness ending in paralysis in mid-life. Detailed analysis showed ~30% loss of large pyramidal neurons in the layer V motor cortex; in the spinal cord, severe demyelination was accompanied by oligodendrocyte injury, protein aggregation, astrogliosis and microgliosis, and elevation of neuroinflammation. Surprisingly, there was no loss of lower motor neurons in the lumbar spinal cord despite the complete paralysis of the hindlimbs. However, denervation was detected at the neuromuscular junction. These results demonstrate that low-level TDP-43 overexpression can cause diverse aspects of ALS, including late-onset and progressive motor dysfunction, neuroinflammation, and neurodegeneration. Our findings suggest that persistent modest elevations in TDP-43 expression can lead to ALS and other neurological disorders involving TDP-43 proteinopathy. Because of the predictable and progressive clinical paralytic phenotype, this transgenic mouse model will be useful in preclinical trial of therapeutics targeting neurological disorders associated with elevated levels of TDP-43.
Increased protein citrullination (PC) and dysregulated protein arginine deiminase (PAD) activity have been observed in several neurodegenerative diseases. PC is a posttranslational modification catalyzed by the PADs. PC converts peptidyl-arginine to peptidyl-citrulline, thereby reducing the positive charges and altering structure and function of proteins. Of the five PADs, PAD2 is the dominant isoform in the central nervous system (CNS). Abnormal PC and PAD dysregulation are associated with numerous pathological conditions, including inflammatory diseases and neurodegeneration. Animal model studies have shown therapeutic efficacy from inhibition of PADs, thus suggesting a role of PC in pathogenesis. To determine whether PC contribute to amyotrophic lateral sclerosis (ALS), a deadly neurodegenerative disease characterized by loss of motor neurons, paralysis, and eventual death, we investigated alterations of PC and PAD2 in two different transgenic mouse models of ALS expressing human mutant SOD1G93A and PFN1C71G, respectively. PC and PAD2 expression are altered dynamically in the spinal cord during disease progression in both models. PC and PAD2 increase progressively in astrocytes with the development of reactive astrogliosis, while decreasing in neurons. Importantly, in the spinal cord white matter, PC accumulates in protein aggregates that contain the myelin proteins PLP and MBP. PC also accumulates progressively in insoluble protein fractions during disease progression. Finally, increased PC and PAD2 expression spatially correlate with areas of the CNS with the most severe motor neuron degeneration. These results suggest that altered PC is an integral part of the neurodegenerative process and potential biomarkers for disease progression in ALS. Moreover, increased PC may contribute to disease-associated processes such as myelin protein aggregation, myelin degeneration, and astrogliosis.
BACKGROUND: Family planning is a proven cost-effective intervention that has contributed to women empowerment and overall human development. Demand factors and women’s expectations and experiences at health facility for family planning services may influence their uptake and utilisation of these services. Increased awareness and positive community perception and quality of family planning services that meet clients’ expectations may greatly improve utilization. The aim of this study was to identify ways to improve family planning service users' experience at primary health care centres towards improving utilization of family planning services in two northern Nigerian states. METHODS: This qualitative study was part of a larger operations research that explored married women’s and service providers’ perception of quality of care along the RMNCH pathway to inform improvements in service delivery. The study utilised Experience-based co-design (EBCD) methodology that employed qualitative methods to explore clients and service providers’ experiences of healthcare services. A total of 92 IDIs and 4 FGDswere conducted in two communities each in Kano and in Yobe states. ‘Touch points’ from service providers’ and respondents’ experiences were extracted using thematic analysis. Joint workshops were further conducted with clients and providers to co-design a user-driven service pathway to improve service utilization. RESULTS: Key 'touch points' from providers’ experiences included stock out of family planning commodities, inadequate equipment and infrastructure and cultural and religious believes that prevent utilization of family planning services. In addition, clients reported challenges securing husband permission to utilize services, poor provider attitude and lack of female providers at health facility as obstacles to service utilization. Co-designing a service improvement plan by service providers and clients that involved increasing community awareness about the benefits of family planning by service providers, improving providers’ attitude, increasing family planning outreach and promoting men involvement in family planning programmes. CONCLUSION: EBCD provides a platform that make clients active contributors to family planning service improvement plans at the health facility thereby ensuring provision of quality services that meet the need of women.
ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.
Objectives The human body physiology rapidly changes and adapt to several environmental stimuli, including light. Abnormal artificial light exposures have been shown to affect sleep cycle, cognition, and mood. Although studies have reported inconsistent effects of short-term or constant long-term light exposures, human exposures to artificial lights occur at varying, unpredictable times and duration daily. Here, we studied the effects of long-term unpredictable light exposure on learning, memory, oxidative status, and associated cytokines in rats. Methods Artificial lighting was provided using an array of white light-emitting diodes coupled to a microcontroller that switches them on or off at unpredictable times and duration (light intensity = 200 ± 20 lx). Within the last eight days of 40 days exposure, animals were subjected to open field test, Morris water maze, and novel object recognition behavioral paradigms. Brain levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase, reduced glutathione (GSH), glutathione S-transferase (GST), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF) were assayed. Results Exposed rats showed impaired spatial learning and memory (p<0.05), but no changes in object recognition memory or locomotor activity. Oxidative stress analyses also revealed significant changes in the concentrations of MDA, SOD, catalase, and GSH levels (p<0.05), not GST. Similarly, there was an increased TNF-α expression (p<0.05), not VEGF. Conclusions We conclude that oxidative stress is involved in memory impairment in rats exposed to prolonged unpredictable lights, which again suggests the detrimental effects of extended light exposure on the nervous system.
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