GDNF not neuroprotective if a-synuclein is present


#1
http://brain.oxfordjournals.org/content/134/8/2302.full.pdf

#2
I didn't read the pdf in detail but in the end it looks like PD models that are used are not a good representation of PD. When PD is caused by MPTP it seems GDNF indeed is neuroprotective. However, when the PD is caused by alpha-synuclein GDNF is not neuroprotective. This is a frightening conclusion.

#3
you would think that anyone now using mptp would have to stop?
i believe rats as a whole have their limitations hence monkeys.
all adding to the cost of experiments?

#4
The authors point out that the other nerve growth factors MANF, neuritin and CDNF have also been tested in the toxin models of PD. They draw the conclusion that the toxin induced models cause damage by via free radicals whereas the alpha syn probably kills in a different way. On the bright side, they describe a more reliable model of PD by the overexpression of wild type alpha syn in the rat brain.

#5
Yes, models overexpressing a-synuclein are way more reliable. This also means that AMGEN was not wrong when they decided to stop GDNF. As most PD patients have a-synuclein, GDNF couldn't work. This also puts big question marks towards MANF and Ceregene. Suddenly, neurotrophic factors don't seem like they are going to be a cure. I put all my hopes on LMTX for the moment. LMTX is known to remove a-synuclein clumps.

#6
I don't know. I am very sceptical about the article claiming GDNF doesn't work in presence of a-synuclein. Here is why:

- http://www.4-traders.com/BRAINSTORM-CELL-THERAPEUT-146414/news/Brainstorm-Cell-Therapeutics-Inc-BrainStorm-s-Outstanding-ALS-Clinical-Data-Chosen-to-Kick-Off-the-15587338/

Neurotrophic factors have been shown last summer to significantly help people woth ALS. ALS is also the consequence of a misfolded protein.

- CERE-120: Though the clinical phase 2 didn't show spectacular results, it did show several positive results. After some patients died they found out that CERE-120 wasn't inserted deeply enough in the brain. Despite that, there was improvement. Therefore, a new clinical phase II was started with much better insertion of CERE-120

I am not saying the article is wrong, but I do have my doubts.

But 1 thing is for sure, they shouldn't only do their tests on rodents with MPTM induced PD.

#7
on the bright side - knowing what doesnt work diverts efforts into those channels that will work. knowing that a model is dubious is better than carrying on using it.

or is that too pollyannaish?

#8
Of course it is good to know if things don't work. But you have to be absolutely sure about this. If this is true, then I have low hopes for Cogane.

I also think at the moment science has quite a good idea of which genes lead to PD. So in theory they could make different mouse models based on these faulty genes and experiment on all of them instead of just taking a normal mouse and poison its brain. Maybe some meds work on people with faulty gene A, but not on people with faulty gene B. There is no reason to assume that there should be a substance that works for all kinds of PD.

The same is true for neuroprotective agents. There was a recent study based on induced pluripotent stem cells that showed rapamycin was neuroprotective for people with LRRK2 mutation, but not for people with PINK1 mutation. This means that all the neuroprotective studies till now have been a big waist of money. I wonder how many agents were discarded because of negative results, but that were neuroprotective for a specific subset of PD patients with a common faulty gene. I think they should re-analyze the data they obtained and do a DNA test of all participants and verify whether maybe they can find a subset in the PD population for which these substances were neuroprotective.

#9
The good thing is that we will know soon for sure whether brain neurotrophic factors are neuroprotective. Results of CEREGENE phase II are expected early 2013, which must be soon.

http://www.ceregene.com/press_051712.asp

#10
Some more proof of a-synuclein presence :

http://7thspace.com/headlines/431004/mitochondrial_quality_dynamics_and_functional_capacity_in_parkinsons_disease_cybrid_cell_lines_selected_for_lewy_body_expression.html

#11
the full article is quite technical but does have some peculiar results.
http://www.molecularneurodegeneration.com/content/pdf/1750-1326-8-6.pdf

the role of lewy bodies seem to be called into question - sometimes they seem to improve the cell! mitochondria seems to be extremely important. i need to re-read it - it is very detailed and technical but getting right down to the nittygritty of what is happening in cells.
if someone qualified would care to comment it would be gratefully received.

#12
I am completely unscientific, it would be great if this could be explained in very simple terms?

#13
IMHO ........the paper is providing evidence that mitochondrial DNA can originate PD, in some cases by adversely affecting performance of the mitochondria, in other cases by an unknown mechanism. The authors point out that this doesn't mean that PD always originates in the mitochondria. There seems to be a growing consensus that PD is a network disease. If you imagine a software programme with negative and positive feedback loops, then an error at critical points along it will cause it to malfunction (without neccessarily collapsing entirely). So in the same way PD could be a fault in the expression of alpha sync, in the phosphorylation of a protein to activate it, in the efficient removal of a damaged protein, of the construction of a mitochondrion and so on. And of course, one might need different agents to alleviate the disease depending on where the mallfunction is.........

#14
Hi V
i may go wrong in this!
the tests were done on cloned cells from pd people in the lab.
they added genes to increase lewy body (LB) formation.
some cells with LBs slowed down, others got more energy. LBs may be rubbish bins for tidying up bad alpha-synuclein (AS). AS is like a ribbon that has to be folded the right way to work. In PD the folding is stuffed. So these misfolded AS are clumped together into LBs (badly folded ribbons put in the rubbish bin!). I think the point is that LBs may not cause harm to the cell but be the result of it trying to fix things. I also may have misunderstood!
mitochondria (MC) is the AA battery of the cell. the nature of MCs seems to have a big effect on how the cell handles the AS.
so cells with good batteries are better and putting badly folded ribbons in the rubbish.
or i may be completely wrong!

#15
i think we said the same thing :grin:

#16
Thank you that's very good, I lean towards the arts, so visualising your explanation is very helpful. So the reasearch was hoping that GDNF would help, but now think it won't? :smile:

#17
the original article says that.
when rats are given a chemical similar to paraquat they develop symptoms like pd.
gdnf helps with this, but doesn't help with real pd which involves AS.

imho it also might be a reason to think that pesticides are not the problem - unless pesticides also cause AS misfolding.

#18
Hello everyone

Really interesting thread. :smile:

Turnip and Bartobob have explained why Parkinson's researchers are so interested in mitochondria and Lewy bodies brilliantly, but if you'd like to find out more we're funding lots of research investigating them.

A couple of examples:

Changes in mitochondrial DNA in Parkinson's
http://www.parkinsons.org.uk/pdf/F-1202_Hudson_plain-english-summary.pdf

Are Lewy bodies the bad guys in Parkinson's?
http://www.parkinsons.org.uk/PDF/H-1001_Mason_plain_english_summary.pdf

Hope you find them interesting.

Best wishes

Claire
(Parkinson's UK Research team)