[Neuroscience] Re: Carotenoid Transport into the RPE

John H. via neur-sci%40net.bio.net (by johnh from goawayplease.com)
Tue Dec 4 19:56:41 EST 2007

"Glen M. Sizemore" <gmsizemore2 from yahoo.com> wrote in message 
news:4755969a$0$25349$ed362ca5 from nr2.newsreader.com...
> "John H." <johnh from goawayplease.com> wrote in message 
> news:13laqukj08fmg6f from corp.supernews.com...
>> 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 ....
> Hi John. I'm not sure I can help the sort of subtleties you might have in 
> mind. Remember, behavior analysts eschew the use of statistics but, of 
> course, I published in journals that require inferential statistics so I 
> have used them - usually repeated measures ANOVA. I know that you were 
> probably just making conversation, but far be it from me to pass up a 
> chance to bad mouth inferential statistics.

Certainly not Glen, I really have to get on top of this because a great many 
epidemiological studies I've looked at come up with some weird and often 
contradictory assertions. I suspect people are placing far too much 
significance of p values, and RRs seem to be all over the place. Beta 
carotene is a real confounder here, the cellular studies clearly indicate 
that in Stargardts, and possibly even Adult macular degeneration, high beta 
carotene is a risk. Yet the epidemiological studies are contradictory on 
this point, so now I'm trying to convince some clinicians not to boost the 
child's beta carotene, there is absolutely no biochemical or cellular logic 
for this.

It isn't just a matter of the mathematics, it also a matter of sampling. For 
me at least, there is something very suspicious about how conclusions can 
change so markedly just because 'n' changes. It seems to me statistics is a 
useful but still blunt instrument and too often people let statistical 
algorithms get in the way of logic. Even what you have said below is a 
relief, it suggests that I thinking in the right direction. Not the first 
time this has happened to me, perhaps I should be more confident in my 
thinking because often it seems my doubts about my logic should be directed 
at the logic of others. Aaah even in this iconoclast the Authority Fallacy 
holds some sway ....

Thanks, you have always been very helpful and it is great to see someone of 
your intellectual and professional stature proffering their expertise, this 
quality seems to be increasingly rare in the world these days.

DRD2 - just me playing around with perservation, the linkage between 
psychosis and intellectual creativity, and the often frequent need, when 
approaching problems of these complexity, to be obsessed to the point of 
near madness in order to adequately think about it.

I've worked my guts out on this because my friends have a great 11 year old 
girl and stargardts moves so quickly that time truly is of the essence here. 
My problem in these days, and my principle area of interest, 
neurodegeneration, is I really need a lab ... .

Yes, real shame Olea is away. Haven't seem him for months but he always has 
good input.

Be well my friend,


One of the weird things about p-values
> is that if you reject the null-hypothesis, the p-value becomes, in a 
> sense, meaningless! This is because a p-value gives the probability of 
> obtaining differences between two groups that are equal to or more extreme 
> than what you obtained GIVEN THAT THE NULL-HYPOTHESIS IS TRUE! But if you 
> reject the null-hypothesis on the basis of the p-value, what is the 
> quantitative meaning of the p-value? Many people think that the p-value 
> "gives the likelihood that the data you obtained are due to chance," but 
> that is the equivalent of saying that it is the probability that the 
> null-hypothesis is true given the data. But, as I have just described, 
> that is not what a p-value gives - it gives the probability of obtaining 
> the data given that the null hypothesis is true! This does not mean that a 
> small p-value should not cause you to reject the null-hypothesis, but as I 
> said in a previous post, rejecting the null hypothesis becomes 
> increasingly likely as a function of sample size! I am increasingly 
> becoming enamored with Beyesian statistics thanks to the 
> unfortunately-absent Michael Olea. That guy is really smart (but I think 
> praise makes him somewhat uncomfortable). Beyesian statistics do, in fact, 
> give you the p that your hypothesis is true given the data. Another thing 
> that people think is that, if the p-value is really small, repeating the 
> experiment is likely to reproduce the results of the first, but this is 
> not true, as far as I can see. The only way to show that a finding is 
> reliable is to replicate it. But a lot of journals discourage the 
> submission of experiments that solely function as replications! 
> Anyhow...speaking of smart, you should be proud of your scientific 
> abilities. BTW, I don't think that I ever saw the abbreviation DRD2 and 
> had to Google it. I suspected it was a DAergic D2. Do you think you need a 
> D2 antagonist for migraine or psychosis? I know what you mean though - I 
> have thought about certain topics on and off for decades, and sometimes 
> cannot abandon the problem for months at a time.
> Good luck in your endeavors,
> Glen
>> Someone take these dreams away .... they keep calling me(Dead Souls, Joy 
>> Division)
>> John.

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