[Neuroscience] Carotenoid Transport into the RPE

John H. via neur-sci%40net.bio.net (by johnh from goawayplease.com)
Tue Dec 4 10:01:16 EST 2007

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 


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