4 research outputs found
A proposed role for efflux transporters in the pathogenesis of hydrocephalus
Hydrocephalus is a common brain disorder that is treated
only with surgery. The basis for surgical treatment rests on
the circulation theory. However, clinical and experimental
data to substantiate circulation theory have remained inconclusive.
In brain tissue and in the ventricles, we see that
osmotic gradients drive water diffusion in water-permeable
tissue. As the osmolarity of ventricular CSF increases
within the cerebral ventricles, water movement into the
ventricles increases and causes hydrocephalus. Macromolecular
clearance from the ventricles is a mechanism to
establish the normal CSF osmolarity, and therefore ventricular
volume. Efflux transporters, (p-glycoprotein), are
located along the blood brain barrier and play an important
role in the clearance of macromolecules (endobiotics
and xenobiotics) from the brain to the blood. There is clinical
and experimental data to show that macromolecules
are cleared out of the brain in normal and hydrocephalic
brains. This article summarizes the existing evidence to
support the role of efflux transporters in the pathogenesis
of hydrocephalus. The location of p-gp along the pathways
of macromolecular clearance and the broad substrate
specificity of this abundant transporter to a variety of different
macromolecules are reviewed. Involvement of p-gp
in the transport of amyloid beta in Alzheimer disease and
its relation to normal pressure hydrocephalus is reviewed.
Finally, individual variability of p-gp expression might explain
the variability in the development of hydrocephalus
following intraventricular hemorrhage
Stac3 is a component of the excitation–contraction coupling machinery and mutated in Native American myopathy
Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca2+ from internal stores to initiate muscle contraction. Defects in EC coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the EC coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca2+ imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation-contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 as the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling. These findings enhance our understanding of both excitation-contraction coupling and the pathology of myopathies