Fair warning: I've had very little time(<2 weeks) to research and think
about this so don't be surprised if I am blundering along here.
I'm trying to track down the following:
Whether or not there are differing transporters into the rod and cone cells,
and the RPE cells, for the pro-vitamin A carotenoids\retinoids and the
non-pro ones, lutein and zeaxanthin.
Can anyone help???
The retinoids go off into the visual cycle, in STGD(stargardt) there is an
accmulution of retinoids in both the ROS and in the lipofuscin in the RPE.
There is also some evidence to suggest a lack of L and Z in the RPE for STGD
patients. I suspect that the ABCA4 product, Rim protein, may have a
preferential transport of retinoid products, particularly those with PE
component, but I'm beginning to wonder if there if there is another
transport function here, that of L and Z into the RPE, being depleted either
by the lipofuscin products, which clearly have a significant retinoid
component, or if the Rim protein also serves a role of transporting L and Z
into the RPE. The problem is that Rim protein, as currently understood,
appears to be a specific product of the rod and cone cells.
The current paradigm for STGD goes like this:
The Rim protein(protein from ABCA4) is dysfunctional, it transports shed ROS
to the RPE for "reprocessing" and the product of the same is purportly then
transported back to the ROS. Yet if Rim protein is a product of rod and cone
cells, and in STGD the lipofuscin is present in the RPE, not the rods and
cones, and if RPE cells first die, this seemingly precipitating
photoreceptor death, then shouldn't we expect to see aggregations primarily
in the rods and cones, not the RPE? It don't make sense.
It might go like this: the Rim protein has two ATP binding clefts, the
transport across cell membranes is ATP dependent, so perhaps the relevant
alleles impact on ATP capture or hydrolysis. So the ROS fragments are
transported to a RPE cd36 receptor where they can be scavenged, but it may
be the case that further ATP is required for transport to the lysosomes
within the RPE to initiate degradation. I am too ignorant about biochemistry
to know whether or not ATP can be transported through a cell membrane via an
ABC transporter and even if that is possible do lysosomes require ATP from
this source or are these ATP independent processes. We're awating genetic
testing results but for now I'm assuming ATP involvement because there is
good evidence to suggest that enhancing mitochondrial function can not only
prevent aggregation but in AMD at least even reduce pre-existing aggregates.
It may not even be an ATP issue, allele variation may be related to the
tranporter segment that binds the retinoid proteins. The incomplete
transport may then allow oxidation via light which exposes hydrophobic
cores, allowing aggregation, preventing adequate transport, perhaps even
"clogging" the RPE cd36 scavenger receptor, so the process goes downhill
from there. Fascinating problem, very fucking difficult, driving me nuts.
So then, can anyone point me to a good article on how the ROS is
constructed, what are its constitutents, and are L and Z present in the
photoreceptor cells or are L and Z very much located in the RPE?
Sort of an academic exercise, asked by friends to help with their daughter
recently diagnosed with STGD. My role there mostly over but now I'm
perservating on the bloody thing. See, a little brain damage goes a long way
... to Hell and back. Hey Glen, if you got this far, I really could do with
a lesson in the finer subtleties of statistical analysis! I suspect that
after this I'm also going to need a DRD2 antagonist ....
Someone take these dreams away .... they keep calling me(Dead Souls, Joy