Is there a continuum from personality disorder to dementia, and if so how come? Maybe a DNA binding protein containing lots of phosphates provides the energy for all sorts of rogue process to mess with DNAs and neurons. And, it looks like TDP-43 self-assembles into gunky fibrils, that clog up the glia and throw a wrench into myelin manufacture. That could cause white matter disconnects in the brain.
Not to gloat. Ok to gloat: that ties up my “psychopaths are white matter challenged” theory pretty well.
If psychopathy is really a TDP43-proteinopathy, such that this protein forms fibrils that lead to white matter disconnects, then I was right during the 2008 and 2009 Neurological Correlates White Matter Days posts (White Matter days randomly being named after department store White Flower Days, the January sales where sheets and towels are on sale).
Behaviorally, psychopathy comes pretty close to frontotemporal dementias, except there are no motor function disruptions, usually, and, people are probably born as psychopaths. Yet, the personality dimensions get worse with age. I was thinking the whole thing related to trinucleotide repeat expansions (a la Fragile X premutations). When you think about all that’s involved in getting the potential mutations or expansions or transposable elements or epigenetic machinery or microsatelites to get their act together, that takes energy. Or maybe it’s tau, and tau takes energy. And, remember the ATP–>ADP of the biology classes you slept through in high school? Yes it’s the phosphates that are the little engine fuel particles.
So. Where do the phosphates come from?
A new player (new to me, at least): TDP-43, Tar DNA binding protein 43. This protein is correlated with frontotemporo dementias and also ALS (Amylateral Sclerosis, Lou Gerhigs’ disease).
TDP-43 binds to DNAs and contains lots of phosphorylation sites at its C-terminus. There’s like 18 on the C-terminus alone. And, to make it more suspicious, TDP-43 c-termini is found in ALS cerebral spinal fluid.
This is not to say that making people disagreeable is all the phosphates do for a living. The phosphates may be important to energize the exon-skipping or to shuttle the protein around in the cytoplasm, but it doesn’t need all those phosphates just for that, I opine. Maybe the C-terminus gets chopped off and sprinkles the phosphates around. That powers up all the other stuff that turns rogue DNAs into rogue people.
If that’s the case, then here’s a study that further explains why psychopaths enjoy power – they are dopamine challenged: TDP-43 is found in people with dementia, and a gene transfer study demonstrated that there is a dosage effect the more you add. TDP-43 starts off by eliminating dopamine neurons in the substantia nigra, and their axons in the striatum. This could explain the video-game obsession that psychopaths have with destroying other people , the lack of dopamine hits. While more TDP-43 results in motor-degeneration symptoms, there are other reasons why TDP 43 could be the ignition for dementia and, by extension, for psychopathy.
Update 4/21, more research on TDP-43 C-terminus: It turns out that TDP-43 crystalizes as a dimer – two molecules put together. This is not that unusual for a protein. But here, TDP-43 has 2 “RRM” or DNA/RNA binding sites, so a dimer has 4 RRM sites. Huh. Must bind pretty tight to the DNA.
The crystalline form of the dimeric molecule is very thermostable, up to 85°C. The C-terminus is also instrumental in the “exon skipping” of a gene involved in cystic fibrosis.
TDP-43 proteinopathy is an aggregate of TDP-43 in cytoplasm, and thought to play a role in the pathologies of ALM and frontal temporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The protein forms fibril-like clumps in cells in the nervous system, like, the brain.
I think this is really interesting from a thermoregulation point of view. Squalene, one of the main fatty acids in the brain in brain lipid/cholesterol synthesis, and necessary for mylin formation, has a melting point of roughly the temperature you get to when you have an untreated fever. Yet, if it is unable to melt because it is infiltrated with TDP-43 fibrils that are highly thermostable, then your brain lipid metabolism is all gunked up, and the sterol biosysnthesis pathways and myelin pathways are messed up. If the glia, that contribute to myelin, are infiltrated, then myelin production may be spotty — and there may be the white matter disconnects that sociopaths/psychopaths seem to have.
So, the drug development mod would be an agent that binds to the TDP-43 C-terminus, maybe. And gets into the blood brain barrier. Probably a pegylated peptibody-ish mimetic could do that. (If you pegylate, it gets into the brain. As an aside, how come in high school, we learn that LSD stays in the brain for decades, and we may be old, like, 25, and suddenly have a flashback — yet, no one figured out how LSD gets past the BBB so the brain drug delivery crowd can use it? I digress.) It’s probably easier to bind to the TDP-43 itself, rather than a DNA target, although perhaps a histone or other DNA binding protein may be the key. But who wants to fool with a DNA binding protein in the FDA? No one. Especially not in the brain. Better to stick with an agent selective for the protein. Plus, this gives you a little lee way to have just enough TDP-43, so it does what it’s supposed to do, without messing up anything else. OK, I’m done with the drug delivery wonkishness.
Abstract below the jump
Tatom JB, Wang DB, Dayton RD, Skalli O, Hutton ML, Dickson DW, Klein RL., “Mimicking Aspects of Frontotemporal Lobar Degeneration and Lou Gehrig’s Disease in Rats via TDP-43 Overexpression,” Mol Ther. 2009 Apr;17(4):607-13. Epub 2009 Feb 17. doi:10.1038/mt.2009.3
Since the discovery of neuropathological lesions made of TDP-43 and ubiquitin proteins in cases of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), there is a burst of effort on finding related familial mutations and developing animal models. We used an adeno-associated virus (AAV) vector for human TDP-43 expression targeted to the substantia nigra (SN) of rats. Though TDP-43 was expressed mainly in neuronal nuclei as expected, it was also expressed in the cytoplasm, and dotted along the plasma membrane of neurons. Cytoplasmic staining was both diffuse and granular, indicative of preinclusion lesions, over 4 weeks. Ubiquitin deposited in the cytoplasm, specifically in the TDP-43 group, and staining for microglia was increased dose-dependently by 1–2 logs in the TDP-43 group, while neurons were selectively obliterated. Neuronal death induced by TDP-43 was pyknotic and apoptotic. TDP-43 gene transfer caused loss of dopaminergic neurons in the SN and their axons in the striatum. Behavioral motor dysfunction resulted after TDP-43 gene transfer that was vector dose-dependent and progressive over time. The cytoplasmic expression, ubiquitination, and neurodegeneration mimicked features of the TDP-43 diseases, and the gliosis, apoptosis, and motor impairment may also be relevant to TDP-43 disease forms involving nigrostriatal degeneration.
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