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Tuesday, February 15, 2011

Cellular inclusions - Some Basic Chemistry Of Tauopathy

The estimated amount of glucose required to support the functions of the human brain each day, expressed in  M&M's is : 250.     ~Harpers, October 1989.
~Personally I like the green ones.

Ubiquitin with Lysine tags for destructio
Unlike Alzheimer's disease, the brain tissue of people with FTD - most probably my brain -  does not show plaques and rarely shows tangles. (Some FTD forms actually show both tangles and inclusions and are called "mixed dementia", and some have no inclusions at all, but the symptoms are indistinguishable) Brain tissue from patients with FTD often show cellular inclusions - clumps of protein that build up within brain cells (neurons). The classical cellular inclusion, named a “Pick body” nearly one-hundred years ago, stains positively for a protein called tau. Tau is a protein involved in stabilizing microtubules, proteins that support the structure and shape of neurons. These microtubules are what makes a brain brain-shaped instead of a puddle of fatty goo. About 40% of people with FTD have these tau-positive inclusions. Frontotemporal dementia was once known as "Pick's disease because of the "Picks bodies." The rest have Tau-negative inclusions, or no visible inclusions at all.

The second type of cellular inclusion found in people with frontotemporal dementia is made up of two other proteins called ubiquitin and TDP-43. These inclusions Tau-negative because when the cells are stained to make Tau inclusions visible they are not present. Ubiquitin is a protein that is involved with clearing waste products from the cell, while TDP-43 is a protein involved with making proteins from the instructions contained in DNA. Nearly all patients with FTD and amyotrophic lateral sclerosis (ALS), and most patients with semantic dementia, show these ubiquitin-TDP-43 inclusions.

Ubiquitin is a small regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms. Among other functions, it directs proteins to recycling.
Phosphorylated Serene
Ubiquitin binds to proteins and labels them for destruction. The ubiquitin tag directs proteins to the proteasome, which is an organelle in the cell that degrades and recycles unneeded proteins. This discovery won the Nobel Prize for chemistry in 2004. Ubiquitin tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms. Now ya know.

TAR DNA-binding protein 43 (TDP-43), is a cellular protein which in humans is encoded by the TARDBP gene. TARDBP was originally identified as a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene. Later it was discovered that hyper-phosphorylated, ubiquitinated and cleaved form of TARDBP, known as pathologic TDP43, is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-U) and in Amyotrophic lateral sclerosis (ALS). Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and other types of head injury.

The term "frontotemporal lobar degeneration" (FTLD) is used to describe the specific pathological diseases that result in FTD syndromes. These pathological diseases are distinguished by the specific proteins found within the neuronal inclusions. Most FTLD subtypes are either:

   1. FTLD-tau, which includes Pick’s disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), all of which show tau-containing inclusions or
   2. FTLD-TDP, which includes several subtypes in which TDP-43 containing inclusions are seen. None of them have been given any kool names yet as far as I can find.

Here are 3 main histological subtypes found at post-mortem:
  • tau inclusions (Pick's disease, MAPT mutations, corticobasal degeneration, progressive supranuclear palsy)
  • ubiquitin positive (tau-negative) inclusions - in the majority of cases that have this type of pathology the ubiquitinated inclusions contain a protein called TDP-43. There are four subtypes of this type of pathology described in the recent consensus criteria by Cairns et al.: type 1 with neurites predominantly, type 2 with cytoplasmic inclusions predominantly; type 3 with intranuclear inclusions and type 4 associated with VCP mutations. Not all ubiquitin-positive, tau negative cases stain for TDP-43 e.g. the CHMP2B cases but also other cases: many of these have been very recently recognized to contain the protein FUS.
  •  Dementia lacking distinctive histology (DLDH) - no inclusions - a rare and controversial entity - new analyses have allowed many cases to be reclassified into one of the positively-defined subgroups.
Note that all variations of FTD are classed as Tauopathies at this time, even though some forms seem to have no Tau inclusions. That is probably because Ubiquitinopathies sounds like something that is everywhere. Just my guess, but this nomenclature ids likely to change in the future. It is likely that the current cluster of diseases included as FTD will be split apart according to their underlying chemistry.
    Phosphorolyzation is important in protein degradation.
    Proteasome from above. Colorized.
    • In the late 1990s, it was recognized that phosphorylation of some proteins causes them to be degraded by the ATP-dependent ubiquitin/proteasome pathway. These target proteins become substrates for particular E3 ubiquitin ligases only when they are phosphorylated. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds.
    Phosphorylation is a chemically complex process, but in Tauopathies the issue is that it turns on and off the activity of proteins - which is what it usually does - but with FTD it occurs in the brain cells. phosphorylation has many purposes, not just tagging proteins for transport. But, if a protein is phosphorylized at a certain site on its chain, or maybe several sites, it is marked to be transported away for recycling. If this chemical marking, or tagging, gets screwed up somehow, the proteins may accumulate, and clump together. They may even fold in half, and form tangles. There are many steps in the chemical pathway where phosphorylation is necessary, and something can go wrong at any one of them.

    This is just a very basic and simple overview. There is a lot more information and research on these brain chemistries. This is just a starting point. To find out more details just Google some of the terms like phosphorylation, tauopathies, TDP-43, and ubiquitin. If that doesn't give you a headache, nothing will.

    So, in a couple places I mention that something can go wrong in these complex chemical pathways. Maybe you are wondering things like: What can go wrong? Is there anything I can do to prevent it? Is there anything I can do to reverse it? Here is what I think about that.

    What can go wrong? Lotsa suff! First a gene could mutate, or activate, and start producing broken proteins. If a protein is missing the place where a phosphorylation-tag would be attached, that protein cannot be tagged, or possibly activated, or deactivated. Or a free radical could attach to the place where the phosphorylation-tag should go, and block the protein from being tagged, or activated, or deactivated. Toxins and chemicals can also interfere with normal brain chemistry. Pesticides and some food additives, among others, have been shown to interfere with how the brain works. Those are just a few examples.

    Is there anything I can do to prevent it? Maybe. If its genetic, probably not much can be done without some form of gene-therapy. As for those pesky free-radicals, yes! This is where all of those anti-oxidants come into play. Just about any and every one of them is beneficial. What they do is to attach to the free radical ions floating around, and bind them up so they cannot attach to anything else and screw up the normal healthy chemistry. My personal approach is to mix up the anti-oxidants in my diet and with supplements. I figure that some will be better at cleaning up certain types of ions than others, and that over time a good healthy mix will suppress all of the pesky things. Just my theory, but a healthy diet with some well-chosen supplements isn't going to hurt anything. Neither will trying to avoid and limit exposure to food additives, and other toxic substances.

    Is there anything I can do to reverse it? This is the big unknown. So far I have seen a few very preliminary research studies which have shown some promise. Check out the post on, of all things, pomegranate juice. Some medications are showing some promise also, but none are yet approved for use. The biggest issue I see with reversing the process is that the Tau inclusions are insoluble under normal circumstances. There is some promising research about dissolving Tau. The following is a short item from a very recent study:  : Tau, a microtubule associated protein, aggregates into intracellular paired helical filaments (PHFs) by an unknown mechanism in Alzheimer's disease (AD) and other tauopathies. A contributing factor may be a failure to metabolize free cytosolic tau within the neuron. The buildup of tau may then drive the aggregation process through mass action. Therefore, proteases that normally degrade tau are of great interest. A recent genetic screen identified puromycin-sensitive aminopeptidase (PSA) as a potent modifier of tau-induced pathology and suggested PSA as a possible tau-degrading enzyme. Again, there is hope.

    When they figure this one all out, we will be home free - if we still have enough brain cells left alive to matter by that time. Until then, I am trying to at least slow or stop as much of the progression as possible by trying to make sure my brain cells have what is necessary to carry on healthy chemical reactions, and guessing what to do, take, and eat to promote these healthy reactions. For information on what medications I am taking follow the "drugs" tab at the top of the blog's home page.

    Everything here is my account of what happened to me, or my interpretation of stuff, except what I copied from somewhere else. Wikepedia is a constant source of information. Every case of FTD is different. Keep in mind as you read this that the person who wrote this has dementia. That would be ME.
    Medical Disclaimer.

    Questions and comments are welcome.


        1. Hi

          I'v been reading your blog since my father was diagnosed with FTD and, as you can imagine, I started furiously researching the disease.

          You probably know about progranulin and I just found that the germans might have found a way around it. This just came out Feb 2011.

          Also, the famous nicotinamide effects on the tau of mice's brains are being studied on humans.

          So, FTD is being attacked by all sides.

          Just thought I'd share this with you.
          Hang on in there.

        2. Thanks for your comment, Lucia.

          I really appreciate the article on the quinone-progranulin link. I had seen the article on the "Malaria Drug", but had not really delved into it yet. I already have a post half written on the progranulin and sortilin links to FTLD, so it is a natural fit. Now maybe I can finish it.

          It is nice to see that I am not the only one searching the web for something that may help - and help now - not ten years from now. It gives us hope if nothing else.

          Best wishes to you and yours.

          Some days are better than others.


        3. Lee,
          I'm continually impressed how you make all this scientific/chemistry stuff readable and understandable to a lay person like me. Thank you. I'm learning a lot.

        4. Thanks for the comment, Eileen.

          I am certainly no expert. It took me a couple months just to figure out a small portion of the basic chemistry, and I am still working on it. I also discuss a lot of this with my Neurologist.

          Thanks for the encouragement.