This is new for me. It appears that, in a survey, anti-rejection drugs taken for organ transplants have a very good protective effect against Alzheimers compared to the general population, see bar graph first http below. This should apply to PD as well. The bad news is we have to wait forever for it.

http://content.iospress.com/download...se%2Fjad150065

Could Toning Down Calcineurin Neutralize α-Synuclein? | ALZFORUM

http://www.psychiatryadvisor.com/alz...rticle/419660/

Overall, no matter what the age group examined, the patients who were taking one of the two drugs had far less prevalence of Alzheimer's and dementia than the general public, the researchers reported in the Journal of Alzheimer's Disease. For example, while 15.3% of the general population over the age of 75 had dementia, just over 0.6% of the study group did.

ashleyk said: "This should apply to PD as well."

I think this is a leap too far.

From the 1st link: " ... these results strongly indicate that inhibition of [calcineurin] ... may protect neurons from the damaging effects of amyloid-beta
oligomers."

This, for me, is the essence of the paper. No mention is made of alpha-synuclein, and no mention is made of PD.

From the 2nd link: "When a cell becomes overloaded with alpha-synuclein, calcium surges into the cytoplasm and binds the protein calmodulin, which then activates calcineurin. The phosphatase plucks phosphates from dozens of different proteins."

I can understand that inhibiting calcineurin could very well limit the damaging effects of toxic forms of alpha-synuclein. However, a more direct approach would be to target alpha-synuclein itself, an approach which has been adopted by many other research efforts.

I think that you have made a good point jeffreyn.

There are a few papers out there which suggest similar findings for calcineurin and α-synuclein-mediated neurotoxicity.

This is the most recent free-access one that I can find PNAS Plus: Calcineurin determines toxic versus beneficial responses to α-synuclein.

It is interesting but is mainly based on tissue culture and yeast models.

I believe the current thinking on Alzheimers and PD is that they both are considered a form of prion disease in that plaques are observed in the brain. In the article below, a case is made that anti-rejection drugs like FK506 and cyclosporine have a noticeable effect on A-synulclein and could be very useful in treating PD. See Fig. 3 bar graph. These drugs have been used for years in people with organ transplants to prevent rejection. In this article it is suggested that there is an optimal dose of FK506 to suppress A-synulein (not too little not too much) and that the drug could be taken intermittently.
It's too bad that these FDA approved drugs are not fast tracked into some sort of trial to see how effective they could be in PD and AD. Many are years into these diseases and time is running out.

Calcineurin determines toxic versus beneficial responses to α-synuclein
Because inhibition of calcineurin activity is routinely exploited clinically through the use of FK506 (tacrolimus) as an immunosuppressant, we now suggest that the repurposing of FK506, a compound that readily traverses the blood brain barrier merits investigation in the management of PD. Because it persists in the central nervous system long after systemic effects have resolved (49), intermittent dosing with this already FDA-approved drug could avoid systemic immunosuppression, while still providing a readily implemented, disease-modifying treatment strategy that targets a fundamental mechanism in the pathogenesis of α-synucleinopathies.

I do not know of anybody who argues that AD and PD are prion diseases.

The various prion diseases (Creutzfeldt–Jakob disease among others) arise when prion protein (PrP) misfolds. The misfolded form of PrP has pathological effects. The misfolded form of PrP can catalyse conversion of the normally-folded form of PrP into its misfolded (pathological) form. This leads to an exponential increase in the level of misfolded PrP.

AD and PD are both protein misfolding diseases. In AD the main suspect is Aβ (there are probably others). Aβ can misfold, which leads to the formation of amyloid - this is why insoluble amyloid plaques are characteristic of AD. The evidence suggests that insoluble amyloid plaques containing Aβ are relatively inert - what does the damage is soluble Aβ complexes along the amyloidogenic pathway though the mechanism(s) of this are controversial. There is no evidence that I know of that the misfolded form of Aβ can catalyse conversion of other molecules of it into the misfolded form, as happens in prion diseases.

PD is similar - there is good evidence that misfolded α-synuclein is neurotoxic. However, I don't know of any evidence that misfolded α-synuclein can catalyse conversion of its normal form into a misfolded form, as in the prion diseases.

kiwi33 said: "I do not know of anybody who argues that AD and PD are prion diseases."

I think you may have just walked into a minefield kiwi33!

For example, have a look at this comment on PubMed Commons, from just a few days ago (about half way down the webpage):

The prion model for progression and diversity of neurodegenerative diseases. - PubMed - NCBI

Prion, prion-like, transcellular prionoid, ... I just hope they can get the terms sorted out ASAP!

Here is another relevant (and recent) reference:

Targeting α-Synuclein as a therapy for Parkinson's disease: The battle begins - Olanow - 217 - Movement Disorders - Wiley Online Library

(It's behind a paywall, but you can preview the 1st page for free. If you register as a patient or carer (patientACCESS), US$3.50 is the price you pay for the complete article.)

Thanks for those links jeffreyn, very interesting.

I have "walked across minefields" often when thinking about protein (mis)folding with my colleagues and may do so again.

I think that the critical experiment to show whether misfolded proteins other than PrP have prion-like properties is to use a mouse knock-out model. For example, one could make (say) α-synuclein KOs and then challenge them with misfolded α-synuclein. The prediction is that not much will happen to the KOs but wild-type mice will get sick because of the infectious (prion-like) properties of misfolded α-synuclein. I don't know if this or similar has been done.

This experiment has been done with mouse PrP KOs - they did not respond to the challenge of misfolded PrP compared to WT mice, who became sick. I heard about this at a conference - the speaker, somewhat flippantly, summed it up with the last slide; "PrP KO mice are OK.".

This is personal for me. A much-loved uncle of mine in NZ died from PD a couple of years ago. My job, apart from offering family support, was to translate what his care team told him into English.

I think that it would be best if investigators of the various protein misfolding diseases focused on mechanisms without being unduly fussed about "angels on a pinhead" arguments about prions.

ashleyk said: "It's too bad that these FDA approved drugs are not fast tracked into some sort of trial to see how effective they could be in PD and AD. Many are years into these diseases and time is running out."

Okay, now I see where you are coming from.

I don't disagree with you. It seems to me that it would indeed be a good thing if some researcher took the initiative and sought funding for a trial of one or more of these drugs in PD and AD, similar to what is happening in the case of nilotinib.

As you say, time is running out for many PWPs and PWAs.

kiwi33 said: "I don't know if this or similar has been done."

My understanding is that the answer is "yes". From my 2nd link: "... these findings were not seen in a-synuclein-null animals, consistent with the need for host a-synuclein to participate in permissive templating (or the prion conformer reaction) to sustain a prion-like chain reaction."

Yes, that's right, I broke into my piggybank and spent some money!

I began this thread by casually stating that PD is a form of prion disease, something I remember reading about. If one does a search of "PD and prion", a lot of information comes up.
Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein | Science
Transcellular propagation of protein pathogens, reminiscent of the spread of viruses, represents an unprecedented concept of disease. It is now known to extend beyond CJD, to include AD and PD, which are the most common neurodegenerative diseases. For all three diseases, there is a long prodromal phase, during which neurodegenerative changes develop and eventually lead to brain dysfunction. The interval between the formation of the first protein inclusions and the appearance of disease symptoms may offer a therapeutic window, provided sufficiently sensitive diagnostic techniques can be developed. Other protein pathogens, such as aggregates of TDP-43 and mutant superoxide dismutase 1, exhibit similar properties (134–136).

The point I was trying to bring to this forum is that, to me, this is new and anti-rejection drugs for the hopeful treatment of PD could be a game changer even if it's not a cure. And along with Nilotinib maybe it could be piggy backed with the forthcoming trials on Nilotnib. They are both FDA approved drugs and should move a lot faster thru the trials.
I am going to forward this thread to the Fox Foundation and others.