397 research outputs found
Amyotrophic lateral sclerosis-associated mutant SOD1 inhibits anterograde axonal transport of mitochondria by reducing Miro1 levels
Defective axonal transport is an early neuropathological feature of amyotrophic lateral sclerosis (ALS). We have previously shown that ALS-associated mutations in Cu/Zn superoxide dismutase 1 (SOD1) impair axonal transport of mitochondria in motor neurons isolated from SOD1 G93A transgenic mice and in ALS mutant SOD1 transfected cortical neurons, but the underlying mechanisms remained unresolved.
The outer mitochondrial membrane protein mitochondrial Rho GTPase 1 (Miro1) is a master regulator of mitochondrial axonal transport in response to cytosolic calcium (Ca2+) levels ([Ca2+]c) and mitochondrial damage. Ca2+ binding to Miro1 halts mitochondrial transport by modifying its interaction with kinesin-1 whereas mitochondrial damage induces Phosphatase and Tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin-dependent degradation of Miro1 and consequently stops transport.
To identify the mechanism underlying impaired axonal transport of mitochondria in SOD1-related ALS we investigated [Ca2+]c and Miro1 levels in ALS mutant SOD1 expressing neurons. We found that expression of ALS mutant SOD1 reduced the level of endogenous Miro1 but did not affect [Ca2+]c. ALS mutant SOD1 induced reductions in Miro1 levels were Parkin dependent. Moreover, both overexpression of Miro1 and ablation of PINK1 rescued the mitochondrial axonal transport deficit in ALS mutant SOD1-expressing cortical and motor neurons.
Together these results provide evidence that ALS mutant SOD1 inhibits axonal transport of mitochondria by inducing PINK1/Parkin-dependent Miro1 degradation
The Role of Mitochondria in Amyotrophic Lateral Sclerosis
Mitochondria are unique organelles that are essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is a prevalent feature of many neurodegenerative diseases including motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption of mitochondrial structure, dynamics, bioenergetics and calcium buffering has been extensively reported in ALS patients and model systems and has been suggested to be directly involved in disease pathogenesis. Here we review the alterations in mitochondrial parameters in ALS and examine the common pathways to dysfunction
Implementing quality indicators in intensive care units: exploring barriers to and facilitators of behaviour change
Earthworms increase plant production: a meta- analysis
To meet the challenge of feeding a growing world population with minimal environmental impact, we need comprehensive and quantitative knowledge of ecological factors affecting crop production. Earthworms are among the most important soil dwelling invertebrates. Their activity affects both biotic and abiotic soil properties, in turn affecting plant growth. Yet, studies on the effect of earthworm presence on crop yields have not been quantitatively synthesized. Here we show, using meta-analysis, that on average earthworm presence in agroecosystems leads to a 25% increase in crop yield and a 23% increase in aboveground biomass. The magnitude of these effects depends on presence of crop residue, earthworm density and type and rate of fertilization. The positive effects of earthworms become larger when more residue is returned to the soil, but disappear when soil nitrogen availability is high. This suggests that earthworms stimulate plant growth predominantly through releasing nitrogen locked away in residue and soil organic matter. Our results therefore imply that earthworms are of crucial importance to decrease the yield gap of farmers who can't -or won't- use nitrogen fertilizer
Outcomes in patients with chronic uveitis: which factors matter to patients? A qualitative study
PURPOSE: Outcome measurements currently used in chronic uveitis care fail to cover the full patient perspective. The aim of this study is to develop a conceptual model of the factors that adult patients with chronic uveitis consider to be important when evaluating the impact of their disease and treatment. METHODS: A qualitative study design was used. Twenty chronic uveitis patients were recruited to participate in two focus groups. Data were transcribed verbatim and analysed using thematic analysis in ATLAS.ti. RESULTS: Coding of the transcripts resulted in a total of 19 codes divided over five themes: 1) disease symptoms and treatment; 2) diagnosis and treatment process; 3) impact on daily functioning; 4) emotional impact; and 5) treatment success factors. CONCLUSION: The conceptual model resulting from this study can contribute to the development of future uveitis specific measures in adults
ALS/FTD‐associated FUS activates GSK‐3β to disrupt the VAPB–PTPIP51 interaction and ER–mitochondria associations
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD
Riverhood: political ecologies of socionature commoning and translocal struggles for water justice
[EN] Mega-damming, pollution and depletion endanger rivers worldwide. Meanwhile, modernist imaginaries of ordering `unruly waters and humans' have become cornerstones of hydraulic-bureaucratic and
capitalist development. They separate hydro/social worlds, sideline river-commons cultures, and deepen socio-environmental injustices. But myriad new water justice movements (NWJMs) proliferate:
rooted, disruptive, transdisciplinary, multi-scalar coalitions that deploy alternative river-society ontologies, bridge South-North divides, and translate river-enlivening practices from local to global and vice-versa. This paper's framework conceptualizes `riverhood' to engage with NWJMs and river commoning initiatives. We suggest four interrelated ontologies, situating river socionatures as arenas of material, social and symbolic co-production: `river-as-ecosociety', `river-as-territory', `river-as-subject', and `river-as-movement'. globalThis work was supported by the ERC European Research Council under the European Union's Horizon 2020 research and innovation programme [Riverhood, Grant Number 101002921]; see also www.movingrivers.org.Boelens, R.; Escobar, A.; Bakker, K.; Hommes, L.; Swyngedouw, E.; Hogenboom, B.; Huijbens, EH.... (2023). Riverhood: political ecologies of socionature commoning and translocal struggles for water justice. The Journal of Peasant Studies. 50(3):1125-1156. https://doi.org/10.1080/03066150.2022.21208101125115650
Riverhood: political ecologies of socionature commoning and translocal struggles for water justice
Mega-damming, pollution and depletion endanger rivers worldwide. Meanwhile, modernist imaginaries of ordering ‘unruly waters and humans’ have become cornerstones of hydraulic-bureaucratic and capitalist development. They separate hydro/social worlds, sideline river-commons cultures, and deepen socio-environmental injustices. But myriad new water justice movements (NWJMs) proliferate: rooted, disruptive, transdisciplinary, multi-scalar coalitions that deploy alternative river–society ontologies, bridge South–North divides, and translate river-enlivening practices from local to global and vice-versa. This paper's framework conceptualizes ‘riverhood’ to engage with NWJMs and river commoning initiatives. We suggest four interrelated ontologies, situating river socionatures as arenas of material, social and symbolic co-production: ‘river-as-ecosociety’, ‘river-as-territory’, ‘river-as-subject’, and ‘river-as-movement’
Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation
Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD
C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons
Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and -independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to-motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly-GA cellular uptake and propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species
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