thoughts on hd and pbt2, page-10

DS, you talk of CLK1 control like PBT2 is not already doing that. I am not sure you can draw that conclusion.
A few years back I was corresponding with a US based researcher on the subject and this is part of his reply.

"Clioquinol analogs (hydoxyquinolines) all bind transition metal ions well. These analogs can also inhibit many kinases due to their homology to ATP (adenosine moiety). PBT2 is a decent inhibitor of CLK1 (responsible for the synthesis of ubiquinone) and could potentially regulate mitochondria activity. Clk1+/- mice live longer and healthier."

PBT2 treated mice also live longer and healthier.

I think CLK1 regulation is more a case of when and if Prana get around to investigating this arm of the MOA.

A little more on CLK1 and the ubiquinone it produces.
"Ubiquinone synthesis is controlled by the gene CLK1. Depicted is a mitochondrion with magnification showing the mitochondrial electron transport chain, which is localized within the inner mitochondrial membrane. Electrons are donated to either complex I or complex II by NADH or FADH2. From complexes I and II, electrons are transferred to ubiquinone (Q), complex III, and finally complex IV. Within the ETC, the Q-cycle can be found and is expanded as shown. When Q becomes QH2 or vice versa, the ubiquinone goes through an intermediate form that is a radical: the ubisemiquinones (Q•). The ubisemiquinone radical can donate its free electron to the Rieske Iron Sulfur center, but can also reduce oxygen to superoxide (Formula), the main source of ROS. The CLK1 gene encodes 3-methoxy-6-methyl-5-polyprenyl-benzoquinone-hydroxylase and is required for the synthesis of 5-hydroxy-quinone (5-OH-Q) from DMQ. Mutations of clk1 lead to increased levels of DMQ."

http://genesdev.cshlp.org/content/19/20/2399.long

"Reactive Oxygen Species (ROS) generated by misplacement of electrons from the ETC by ubisemiquinones are quickly and effectively detoxified by both superoxide dismutases and catalases. ROS that are able to escape detoxification can react with larger macromolecules, leading to the appearance of aberrant molecules, such as protein carbonyls or peroxidated lipids, which are dysfunctional and potentially impair processes essential for cell maintenance and survival."

superoxide dismutases are SOD1,2 & 3 which require metals to function, and can be affected by metal homeostasis.
It is starting to look to me like even at mitocondria level the PBT MOA has multiple arms of effect.

The apparent ability of PBT2 to restore the neuron's ability to self regulate iron levels can also be expected to reap benefits and could also be linked to superoxide dismutases.

Superoxide dismutase 1 modulates expression of transferrin receptor.
Danzeisen R, Achsel T, Bederke U, Cozzolino M, Crosio C, Ferri A, Frenzel M, Gralla EB, Huber L, Ludolph A, Nencini M, Rotilio G, Valentine JS, Carrì MT.
Abstract
Copper-zinc superoxide dismutase (SOD1) plays a protective role against the toxicity of superoxide, and studies in Saccharomyces cerevisiae and in Drosophila have suggested an additional role for SOD1 in iron metabolism. We have studied the effect of the modulation of SOD1 levels on iron metabolism in a cultured human glial cell line and in a mouse motoneuronal cell line. We observed that levels of the transferrin receptor and the iron regulatory protein 1 were modulated in response to altered intracellular levels of superoxide dismutase activity, carried either by wild-type SOD1 or by an SOD-active amyotrophic lateral sclerosis (ALS) mutant enzyme, G93A-SOD1, but not by a superoxide dismutase inactive ALS mutant, H46R-SOD1. Ferritin expression was also increased by wild-type SOD1 overexpression, but not by mutant SOD1s. We propose that changes in superoxide levels due to alteration of SOD1 activity affect iron metabolism in glial and neuronal cells from higher eukaryotes and that this may be relevant to diseases of the nervous system."

Iron overload also knocks out P53 DNA protector by causing it to oligomerize into sheets making it ineffective.

It looks to me like PBT2 is hitting the right targets around the mitocondria.

Please feel free to correct anything there.