Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency

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Highlights? Fumarate inhibits Aconitase2 activity via succination of critical cysteine residues ? Endogenous Aconitase2 is succinated and inhibited in FH-deficient cells ? Succination occurs in multiple proteins with roles in diverse cellular processes ? Succination can alter metabolism in FH-deficient cells     

Mortality Risk amongst Nursing Home Residents Evacuated after the Fukushima Nuclear Accident: A Retrospective Cohort Study

Background

Safety of evacuation is of paramount importance in disaster planning for elderly people; however, little effort has been made to investigate evacuation-related mortality risks. After the Fukushima Daiichi Nuclear Plant accident we conducted a retrospective cohort survival survey of elderly evacuees.

Methods

A total of 715 residents admitted to five nursing homes in Minamisoma city, Fukushima Prefecture in the five years before 11th March 2011 joined this retrospective cohort study. Demographic and clinical characteristics were drawn from facility medical records. Evacuation histories were tracked until the end of 2011. The evacuation''s impact on mortality was assessed using mortality incidence density and hazard ratios in Cox proportional hazards regression.

Results

Overall relative mortality risk before and after the earthquake was 2.68 (95% CI: 2.04–3.49). There was a substantial variation in mortality risks across the facilities ranging from 0.77 (95% CI: 0.34–1.76) to 2.88 (95% CI: 1.74–4.76). No meaningful influence of evacuation distance on mortality was observed although the first evacuation from the original facility caused significantly higher mortality than subsequent evacuations, with a hazard ratio of 1.94 (95% CI: 1.07–3.49).

Conclusion

High mortality, due to initial evacuation, suggests that evacuation of the elderly was not the best life-saving strategy for the Fukushima nuclear disaster. Careful consideration of the relative risks of radiation exposure and the risks and benefits of evacuation is essential. Facility-specific disaster response strategies, including in-site relief and care, may have a strong influence on survival. Where evacuation is necessary, careful planning and coordination with other nursing homes, evacuation sites and government disaster agencies is essential to reduce the risk of mortality.     

Ablation of Keratan Sulfate Accelerates Early Phase Pathogenesis of ALS

Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1^G93A mice and GlcNAc6ST-1^−/− mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1^G93AGlcNAc6ST-1^−/− mice exhibited a significantly shorter lifespan than SOD1^G93A mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1^G93A mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1^G93A mice, while this enhancement was attenuated in SOD1^G93AGlcNAc6ST-1^−/− mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1^G93AGlcNAc6ST-1^−/− mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.     

Caldesmon suppresses cancer cell invasion by regulating podosome/invadopodium formation

The podosome and invadopodium are dynamic cell-adhesion structures that degrade the extracellular matrix (ECM) and promote cell invasion. We recently reported that the actin-binding protein caldesmon is a pivotal regulator of podosome formation. Here, we analyzed the caldesmon's involvement in podosome/invadopodium-mediated invasion by transformed and cancer cells. The ectopic expression of caldesmon reduced the number of podosomes/invadopodia and decreased the ECM degradation activity, resulting in the suppression of cell invasion. Conversely, the depletion of caldesmon facilitated the formation of podosomes/invadopodia and cell invasion. Taken together, our results indicate that caldesmon acts as a potent repressor of cancer cell invasion.     

Effects of thin and thick filament proteins on calcium binding and exchange with cardiac troponin C

Understanding the effects of thin and thick filament proteins on the kinetics of Ca(2+) exchange with cardiac troponin C is essential to elucidating the Ca(2+)-dependent mechanisms controlling cardiac muscle contraction and relaxation. Unlike labeling of the endogenous Cys-84, labeling of cardiac troponin C at a novel engineered Cys-53 with 2-(4'-iodoacetamidoanilo)napthalene-6-sulfonic acid allowed us to accurately measure the rate of calcium dissociation from the regulatory domain of troponin C upon incorporation into the troponin complex. Neither tropomyosin nor actin alone affected the Ca(2+) binding properties of the troponin complex. However, addition of actin-tropomyosin to the troponin complex decreased the Ca(2+) sensitivity ( approximately 7.4-fold) and accelerated the rate of Ca(2+) dissociation from the regulatory domain of troponin C ( approximately 2.5-fold). Subsequent addition of myosin S1 to the reconstituted thin filaments (actin-tropomyosin-troponin) increased the Ca(2+) sensitivity ( approximately 6.2-fold) and decreased the rate of Ca(2+) dissociation from the regulatory domain of troponin C ( approximately 8.1-fold), which was completely reversed by ATP. Consistent with physiological data, replacement of cardiac troponin I with slow skeletal troponin I led to higher Ca(2+) sensitivities and slower Ca(2+) dissociation rates from troponin C in all the systems studied. Thus, both thin and thick filament proteins influence the ability of cardiac troponin C to sense and respond to Ca(2+). These results imply that both cross-bridge kinetics and Ca(2+) dissociation from troponin C work together to modulate the rate of cardiac muscle relaxation.     

ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor

Motor neuron degeneration resulting from the aggregation of the androgen receptor with an expanded polyglutamine tract (AR-polyQ) has been linked to the development of spinal and bulbar muscular atrophy (SBMA or Kennedy disease). Here we report that adding 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators, and also increases cell survival by decreasing AR-polyQ nuclear aggregation and increasing AR-polyQ degradation in cultured cells. Intraperitoneal injection of ASC-J9 into AR-polyQ transgenic SBMA mice markedly improved disease symptoms, as seen by a reduction in muscular atrophy. Notably, unlike previous approaches in which surgical or chemical castration was used to reduce SBMA symptoms, ASC-J9 treatment ameliorated SBMA symptoms by decreasing AR-97Q aggregation and increasing VEGF164 expression with little change of serum testosterone. Moreover, mice treated with ASC-J9 retained normal sexual function and fertility. Collectively, our results point to a better therapeutic and preventative approach to treating SBMA, by disrupting the interaction between AR and AR coregulators.