6 research outputs found
Requirement of the CsdA DEAD-box helicase for low temperature riboregulation of rpoS mRNA
The ribosome binding site of Escherichia coli rpoS mRNA, encoding the stationary sigma-factor RpoS, is sequestered by an inhibitory stem-loop structure (iss). Translational activation of rpoS mRNA at low temperature and during exponential growth includes Hfq-facilitated duplex formation between rpoS and the small regulatory RNA DsrA as well as a concomitant re-direction of RNase III cleavage in the 5′-untranslated region of rpoS upon DsrA·rpoS annealing. In this way, DsrA-mediated regulation does not only activate rpoS translation by disrupting the inhibitory secondary structure but also stabilizes the rpoS transcript. Although minor structural changes by Hfq have been observed in rpoS mRNA, a prevailing question concerns unfolding of the iss in rpoS at low growth temperature. Here, we have identified the DEAD-box helicase CsdA as an ancillary factor required for low temperature activation of RpoS synthesis by DsrA. The lack of RpoS synthesis observed in the csdA mutant strain at low growth temperature could be attributed to a lack of duplex formation between rpoS and DsrA, showing that at low temperature the sole action of Hfq is not sufficient to permit DsrA·rpoS annealing. An interactome study has previously indicated an association between Hfq and CsdA. However, immunological assays did not reveal a physical interaction between Hfq and CsdA. These findings add to a model, wherein Hfq binds upstream of the rpoS iss and presents DsrA in a conformation receptive to annealing. Melting of the iss by CsdA may then permit DsrA·rpoS duplex formation, and consequently rpoS translation
Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis
Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following
Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The
increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response
in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental
model of MS, experimental allergic encephalomyelitis (EAE), where blood
–
brain barrier disruption and vascular
remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory
factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since
VEGF naturally enhances neuron resistance to injury and regulates
neural progenitor proliferation, migration, differentiation
and oligodendrocyte precursor cell (OPC) survival and migrati
on to demyelinated lesions. An
giogenesis, neurogenesis and
oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the
preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual
fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic
stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect
of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion
of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should
be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS