Cytoplasmic human TDP-43 mislocalization induces widespread dendritic spine loss in mouse upper motor neurons

Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lowermotor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containingthe DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalizationof TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliestdetectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigatedhow mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracyclineinducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannotenter the nucleus (TDP-43∆NLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH miceto visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WTand controls, TDP-43∆NLS drove a robust loss in spine density in all the dendrite regions of theupper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in thegeneration of network dysfunction in ALS likely through impacting the formation or durability ofexcitatory synapses. These findings are relevant to the vast majority of ALS cases, and providesfurther evidence that upper motor neurons may need to be protected from TDP-43 mediated synapticexcitatory changes early in disease

The High Prevalence of Vitamin D Insufficiency across Australian Populations Is Only Partly Explained by Season and Latitude

Background Inadequate sun exposure and dietary vitamin D intake can result in vitamin D insufficiency. However, limited data are available on actual vitamin D status and predictors in healthy individuals in different regions and by season.Methods We compared vitamin D status [25-hydroxyvitamin D; 25(OH)D] in people &lt; 60 years of age using data from cross-sectional studies of three regions across Australia: southeast Queensland (27&deg;S; 167 females and 211 males), Geelong region (38&deg;S; 561 females), and Tasmania (43&deg;S; 432 females and 298 males).Results The prevalence of vitamin D insufficiency (&le; 50 nmol/L) in women in winter/spring was 40.5% in southeast Queensland, 37.4% in the Geelong region, and 67.3% in Tasmania. Season, simulated maximum daily duration of vitamin D synthesis, and vitamin D effective daily dose each explained around 14% of the variation in 25(OH)D. Although latitude explained only 3.9% of the variation, a decrease in average 25(OH)D of 1.0 (95% confidence interval, 0.7&ndash;1.3) nmol/L for every degree increase in latitude may be clinically relevant. In some months, we found a high insufficiency or even deficiency when sun exposure protection would be recommended on the basis of the simulated ultraviolet index.Conclusion Vitamin D insufficiency is common over a wide latitude range in Australia. Season appears to be more important than latitude, but both accounted for less than one-fifth of the variation in serum 25(OH)D levels, highlighting the importance of behavioral factors. Current sun exposure guidelines do not seem to fully prevent vitamin D insufficiency, and consideration should be given to their modification or to pursuing other means to achieve vitamin D adequacy.<br /