Fatal familial insomnia: mitochondrial and protein synthesis machinery decline in the mediodorsal thalamus.

The expression of subunits of mitochondrial respiratory complexes and components of the protein synthesis machinery from the nucleolus to the ribosome was analyzed in the mediodorsal thalamus in seven cases of fatal familial insomnia (FFI) compared with age-matched controls. NDUFB8 (complex I subunit), SDHB (complex II subunit), UQCRC2 (complex III subunit), COX2 (complex IV subunit), and ATP50 (complex V subunit) expression levels, as revealed by western blotting, were reduced in FFI. Voltage-dependent anion channel (VDAC) and ATP5H were also reduced due to the marked depopulation of neurons. In contrast, a marked increase in superoxide dismutase 2 (SOD2) was found in reactive astrocytes thus suggesting that astrocytes are key factors in oxidative stress responses. The histone-binding chaperones nucleolin and nucleoplasmin 3, and histone H3 di-methylated K9 were markedly reduced together with a decrease in the expression of protein transcription elongation factor eEF1A. These findings show severe impairment in the expression of crucial components of mitochondrial function and protein synthesis in parallel with neuron loss in mediodorsal thalamus at terminal stages of FFI. Therapeutic measures must be taken long before the appearance of clinical symptoms to prevent the devastating effects of FFI.

Altered Mitochondria, Protein Synthesis Machinery, and Purine Metabolism Are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease.

Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt-Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD.

Accumulation of furanocoumarins by Bituminaria bituminosa in relation to plant development and environmental stress.

Bituminaria bituminosa (L.) C.H. Stirton (Fabaceae) accumulates high concentrations of the furanocoumarins (FCs) angelicin and psoralen, which protect against infection and herbivory. The effects on FC accumulation of the exposure of two populations of B. bituminosa to abiotic stress (cold, heat and drought) under field conditions were determined, as well as the effect of temperature under controlled conditions, in hydroponic culture. In field conditions, psoralen and angelicin levels in the leaf dry matter were 400-6000 and 1500-11,000 µg g(-), respectively. There were significant effects of population on the psoralen concentration and psoralen:angelicin ratio. In hydroponic culture, exposure to a diurnal temperature of 33 °C increased FC levels in population Calnegre but not in Llano del Beal, compared with plants grown at 22 °C; however, high summer temperatures in the field (>30 °C) did not coincide with the highest leaf FC levels, since the plants accumulated FCs preferentially in the fruits. Hence, leaf FC levels were higher in winter. Irrigation, to alleviate water stress in the semi-arid conditions, increased the fruit psoralen concentration but produced only minor decreases in leaf FC levels. There was a significant, positive correlation (P < 0.001) between the FC and nitrogen concentrations in the plant organs analysed (both increased in the order: fruits > growing leaves > mature leaves), reflecting their respective contributions to plant fitness. The genetically- and developmentally-regulated accumulation of FCs by B. bituminosa is altered by short-term variations in environmental conditions, particularly temperature.

A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration.

Secreted semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. We screened a peptoid combinatorial library to search for semaphorin 3A inhibitors, and identified a peptoid (SICHI: semaphorin Induced chemorepulsion inhibitor) that blocks semaphorin 3A-chemorepulsion and growth-cone collapse in axons at millimolar concentrations. SICHI inhibits the binding of semaphorin 3A to its receptor complex (neuropilin 1/plexin A1) and semaphorin 3A-induced phosphorylation of GSK3. Chemorepulsion induced by semaphorin 3F or netrin 1 is not blocked by SICHI. We also show that SICHI promotes neural regeneration of damaged axons. We suggest that SICHI, a selective inhibitor of semaphorin 3A, is of therapeutic interest for approaches aimed at promoting axonal regeneration and brain repair.