Tupelo3 said: "You've just described the theory of why c-Abl inhibitors (e.g. Nilotinib) may be neuroprotective."

I would say "a theory" rather than "the theory". There are (at least) several theories.

From my second reference (Brahmachari et al.): "... we report a key and defining role for c-Abl activation in a-synuclein-induced neurodegeneration. In particular, our study implicates that selective inhibition of c-Abl could be neuroprotective."

Here is another one, this time involving the PARIS protein.

Role of Parkin, PINK 1 in protection of dopamine neurons

Jeffrey, my comment was really made tongue-in-cheek. However, if you want to be literal, I believe my comment is actually correct.

All of the research you mention is just support of the same basic theory. Essentially, the two kinases, Parkin and Pink1, add a protein called ubiquitin to PARIS, resulting in it's breakdown. PARIS is critical for proteasome-mediated protein clearance (particularly a-syn) and helps protect against the loss of dopamine neurons. The tyrosine kinase Abelson (c-Abl) is known to interact with many genes, and their protein products. Two of those, specifically, are Parkin and Pink1. c-ABL phosphorylates parkin, which inhibits its ligase activity, leads to substrate accumulation, and interferes with its protection against neurotoxicity. Recent analyses from PD patients and animal models of PD show an increase in the level of c-Abl, suggesting that the gene, and it's kinase, may be dysfunctional in PWP. This leads to the theory that reducing c-abl will reduce the breakdown of other kinases, like Parkin and Pink1, allowing them to function normally in protein clearance. The Brahmachari et al. study you noted demonstrated that deletion of the gene encoding c-Abl reduced α-synuclein aggregation and neurobehavioral deficits whereas overexpression of the constitutively active c-Abl accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. This study was a major component of the the research theory in the protocol for both the Georgetown and MJFF et al new trials.

I know this is an over-simplification, but this is the theory that backs all three of the upcoming trials. What other theories are there behind the use of a c-Abl inhibitor as a neuroprotective agent?

Tupelo3, thanks very much for your substantial response.

I used the word "theory" when perhaps I should have been using the word "hypothesis".

Hypothesis No 1:
During bouts of fever or infection, the mitochondria within dopamine neurons release a specific protein, which is transported to the wall of the cell, where it acts as an antigen, signalling T cells to attack the neuron. This process is normally prevented from occurring by the actions of the proteins Parkin and PINK1, except in PWPs, where the c-Abl enzyme interferes with the normal operation of Parkin.

​Hypothesis No 2:
From your text: "... the theory that reducing c-Abl will reduce the breakdown of other kinases, like Parkin and Pink1, allowing them to function normally in protein [e.g. alpha-synuclein] clearance."

Hypothesis No 3:
Within the dopamine neurons of non-PWPs, PINK1 proteins phosphorylate PARIS proteins, and this then enables Parkin proteins to ubiquitinate PARIS proteins, and this then enables PARIS proteins to be degraded by proteasomes. This keeps the number of PARIS proteins in check, thus ensuring that dopamine neurons are not killed by excess amounts of the PARIS protein. However, in PWPs, c-Abl interferes with Parkin, and this stops Parkin from being able to ubiquitinate PARIS.

All three hypotheses have in common the phosphorylation by c-Abl of Parkin. They all support a general "theory" (or broad hypothesis) that inhibition of c-Abl may be neuroprotective.

Respectfully, in all three of the hypotheses you present the inhibition of c-Abl are the exact same. What you're trying to postulate is what may cause malfunction in the first place. Maybe its environmental like fever, infection, or other toxin. Maybe it's genetic. Maybe it's some other cause we haven't even thought of yet. Nevertheless, in each of your hypotheses, there are no differences once you get to the point oh inhibiting c-Abl. I would be inclined to agree with you if there was evidence, or even a theory (or hypothesis) that c-Abl inhibition reacted differently with genetically mutated Parkin as opposed to environmentally malformed Parkin (associated with idiopathic PD). But, I am not aware of that, at this time.

I think you really are more focused on the theories of the root cause of PD. That goes way beyond any theory or hypothesis as to why c-abl inhibition may be neuroprotective for people with neurological diseases.

Tupelo3, I've read your response several times, but I just can't see how you came to understand my post in that way. I'll try to say the same thing once again, but this time in a different way.

From reference [4]: "While the activity of c-Abl is crucial for proper neuronal development, it appears that c-Abl remains relatively quiescent in healthy adult neurons, and there are few known functions of c-Abl in fully differentiated neurons. In recent years, it has been shown that activation of c-Abl in adult brain occurs in the context of human neurodegenerative disease."

From reference [2]: "c-Abl is a nonreceptor tyrosine kinase that is activated by oxidative and cellular stress"

Just from these two statements, it could be hypothesized that the inhibition of c-Abl might be a worthwhile thing to try.

I have simply outlined three different ways by which the inhibition of c-Abl might (hypothetically) result in protection of dopamine neurons.

Granted, hypotheses 1 & 3 have my name on them, but in each case I have only contributed the bit which says that c-Abl prevents Parkin from performing its normal function. The rest of hypothesis 1 and hypothesis 3 is straight from reference [1] and reference [3] respectively.

[1] Matheoud et al. (2016) Parkinson’s Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation, Cell 166, 314–327, doi: 10.1016/j.cell.2016.05.039.

[2] Brahmachari et al. (2016) Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration, J Clin Invest. doi: 10.1172/JCI85456.

[3] Yunjong et al. (2016) PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival, Cell Reports Volume 18, Issue 4, p918–932, doi: 10.1016/j.celrep.2016.12.090.

[4] Schlatterer et al. (2011) c-Abl in Neurodegenerative Disease, J Mol Neurosci. 2011 Nov; 45(3): 445–452, doi: 10.1007/s12031-011-9588-1.

I guess we'll just have to agree to disagree.

I, too, seem to be germ proof. I haven't had a cold in years since being diagnosed and don't catch them even when everyone around me has a cold or flu.