Tag Archives: Parkinson’s disease

Progress has been slow but not for want of trying

Progress in the sense of therapy for Alzheimer’s disease and Glioblastoma multiforme is essentially nonexistent, and we could use better therapy for Parkinsonism. This doesn’t mean that researchers have given up. Far from it. Three papers all in last week’s issue of PNAS came up with new understanding and possibly new therapeutic approaches for all three.

You’ll need some serious molecular biological and cell physiological chops to get through the following.

l. Glioblastoma multiforme — they aren’t living much longer than they were when I started pracice 45 years ago (about 2 years — although of course there are exceptions).

The human ZBTB family of genes consists of 49 members coding for transcription factors. BCL6 is also known as ZBTB27 and is a master regulator of lymph node germinal responses. To execute its transcriptional activity, BCL6 requires homodimerization and formation of a complex with a variety of cofactors including BCL6 corerpressor (BCoR), nuclear receptor corepressor 1 (NCoR) and Silencing Mediator of Retinoic acid and Thyroid hormone receptor (SMRT). BCL6 inhibitors block the interaction between BCL6 and its friends, selectively killing BCL6 addicted cancer cells.

The present paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3981 – 3986 ’17 ] shows that BCL6 is required for glioblastoma cell viability. One transcriptional target of BCL6 is AXL, a tyrosine kinase. Depletion of AXL also decreases proliferation of glioblastoma cells in vitro and in vivo (in a mouse model of course).

So here are two new lines of attack on a very bad disease.

2. Alzheimer’s disease — the best we can do is slow it down, certainly not improve mental function and not keep mental function from getting worse. ErbB2 is a member of the Epidermal Growth Factor Receptor (EGFR) family. It is tightly associated with neuritic plaques in Alzheimer’s. Ras GTPase activation mediates EGF induced stimulation of gamma secretase to increase the nuclear function of the amyloid precursor protein (APP) intracellular domain (AICD). ErbB2 suppresses the autophagic destruction of AICD, physically dissociating Beclin1 vrom the VPS34/VPS15 complex independently of its kinase activity.

So the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. E3129 – E3138 ’17 ] Used a compound downregulating ErbB2 function (CL-387,785) in mouse models of Alzheimer’s (which have notoriously NOT led to useful therapy). Levels of AICD declined along with beta amyloid, and the animals appeared smarter (but how smart can a mouse be?).

3.Parkinson’s disease — here we really thought we had a cure back in 1972 when L-DOPA was first released for use in the USA. Some patients looked so good that it was impossible to tell if they had the disease. Unfortunately, the basic problem (death of dopaminergic neurons) continued despite L-DOPA pills supplying what they no longer could.

Nurr1 is a protein which causes the development of dopamine neurons in the embryo. Expression of Nurr1 continues throughout life. Nurr1 appears to be a constitutively active nuclear hormone receptor. Why? Because the place where ligands (such as thyroid hormone, steroid hormones) bind to the protein is closed. A few mutations in the Nurr1 gene have been associated with familial parkinsonism.

Nurr1 functions by forming a heterodimer with the Retinoid X Receptor alpha (RXRalpha), another nuclear hormone receptor, but one which does have an open binding pocket. A compound called BRF110 was shown by the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3795 – 3797, 3999 – 4004 ’17 ] to bind to the ligand pocked of RXRalpha increasing its activity. The net effect is to enhance expression of dopamine neuron specific genes.

More to the point MPP+ is a toxin pretty selective for dopamine neurons (it kills them). BRF110 helps survival against MPP+ (but only if given before toxin administration). This wouldn’t be so bad because something is causing dopamine neurons to die (perhaps its a toxin), so BRF110 may fight the decline in dopamine neuron numbers, rather than treating the symptoms of dopamine deficiency.

So there you have it 3 possible new approaches to therapy for 3 bad disease all in one weeks issue of PNAS. Not easy reading, perhaps, but this is where therapy is going to come from (hopefully soon).

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Hillary’s health — you can see a lot by looking

Last night’s debates should put two suggestions about Hillary’s health to rest and gives some evidence for two others. First, she does not have Parkinson’s disease. Second, she does not have epilepsy. Third, her eye movements still show some residua from the stroke of December 2012. Fourth, she may have a mild proximal myopathy.

Now to elaborate.

Parkinson’s disease: Two great things happened in September 1970 — I finished my two years in the Air Force and L – DOPA was released for use in the USA. American neurologists had been reading about the great things it was doing for the disease in Europe for almost 10 years. So when I went back to complete the last two years of my residency, the chief put me in charge of the L – DOPA clinic he’d just set up. So until retirement in 2000, I treated lots of people with it.

As the chief said — Parkinson’s disease is a Yellow Cab disease. If you see a Yellow Cab on the street, you don’t write down the license number, go down to city hall and find that it was registered as a Yellow Cab. You look at it and say “that’s a Yellow Cab”.

Parkinsonians have a rather immobile face (masklike) — Hillary’s face is quite mobile. Their speech lacks the normal musicality of speech (prosody), Hillary’s speech has normal inflection. Parkinsonians have a slow, stiff gait with difficulty initiating it. Hillary has none of this. Finally there is no sign of any tremor.

Epilepsy: Videos of purported seizures are out and about on the internet, particularly one during an interview. I thought that the ones I saw looked rather edited, as though some individual frames had been deleted from the videos. Fortunately last night we had an opportunity to see for ourselves. Toward the end of the debate, she had another episode, during which she shook her head and her shoulders for a few seconds. This happened in real time, so we could run the video recording backwards and forwards. At no time did she appear to be out of contact, and she then continued on with what she was saying without pause. So it’s just something she voluntarily does. It isn’t epilepsy.

Eye movements: Recall that after the stroke in December 2012, Hillary had double vision and had to wear Fresnel lenses to correct it for a few weeks afterwards — pictures of her testifying in congress January 2013 show this. So last night there was a 90 minute opportunity to watch the way her eyes move. They aren’t quite normal – on looking to her left the right eye lags and doesn’t bury the white. Even though Trump was to her right, she turned her head rather than her eyes to look at him, so I only saw her look to her right on a few occasions, but when she did her eyes appeared to move together. No other residua of a brainstem stroke were present such as slurred speech (dysarthria), facial weakness, facial asymmetry.

Proximal muscle weakness: The internist referred to in a previous post noted the following:

“There were shots a month or so ago of her needing help to get up outdoor stairs and also needing a small step-stool to get up into a Secret Service Suburban. My wife and I hop in and out of a Yukon and do not need any step device (they are of comparable age). After a photo of her doing that was published, she started getting in and out of vehicles on the side away from cameras and was also switched to a taller van with a step mounted on the vehicle. In February, press was forbidden by her staff from filming her climbing the stairs to board her private jet.”

He wondered if she could have something like limb girdle dystrophy.

Well, such a dystrophy is certainly possible. Although Hillary  had no difficulty standing for 90 minutes, at the end, she appeared to waddle as she walked toward the moderator.. There wasn’t really enough time to definitely say that she waddled.  It’s worth carefully watching the way she walks in the future.

Why is waddling a sign of mild weakness of the muscles of the pelvic girdle? Believe it or not the buttocks are not a secondary sexual characteristic. The main buttock muscle (gluteus maximus) is so big because it has so much work to do.

Think about what you do when you take a step forward with your right foot. To remain stable, your entire upper body weight must  be strongly plastered to your left hip. You need a strong, large muscle to do this (the gluteus maximus). What happens if the muscle is weak? Your upper body would fall to the right. How would you prevent this? By throwing your upper body to the left, putting its center of gravity there, so it presses on the left hip with greater force. A similar thing happens when stepping forward with the left foot. The net effect is that you waddle, which is what Hillary appeared to do.

It’s worth watching her walk in the future.

Stamina: she was under 90 minutes of stress, and showed no sign of fatigue.

Now, hopefully, back to the science, with a very long (over 1,000 Angstroms) allosteric effect.

Just when you thought you understood neurotransmission

Back in the day, the discovery of neurotransmission allowed us to think we understood how the brain worked. I remember explaining to medical students in the early 70s, that the one way flow of information from the presynaptic neuron to the post-synaptic one was just like the flow of current in a vacuum tube — yes a vacuum tube, assuming anyone reading knows what one is. Later I changed this to transistor when integrated circuits became available.

Also the Dale hypothesis as it was taught to me, was that a given neuron released the same neurotransmitter at all its endings. As it was taught back in the 60s this meant that just one transmitter was released by a given neuron.

Retrograde transmission was just a glimmer in the mind’s eye back then. We now know that the post-synaptic neuron releases compounds which affect the presynaptic neuron, the supposed controller of the postsynaptic neuron. Among them are carbon monoxide, and the endocannabinoids (e. g. what marihuana is trying to mimic).

In addition there are neurotransmitter receptors on the presynaptic neuron, which respond to what it and other neurons are releasing to control its activity. These are outside the synapse itself. These events occur more slowly than the millisecond responses in the synapse to the main excitatory neurotransmitter of the brain (glutamic acid) and the main inhibitory neurotransmitter (gamma amino butyric acid — aka GABA). Receptors on the presynaptic neuron for the transmitter it’s releasing are called autoreceptors, but the presynaptic terminal also contains receptors for other neurotransmitters.

Well at least, neurotransmitters aren’t released by the presynaptic neuron without an action potential which depolarizes the presynaptic terminal, or so we thought until [ Neuron vol. 82 pp. 63 – 70 ’14 ]. The report involves a structure near and dear to the neurologist the striatum (caudate and putamen — which is striated because the myelinated axons of the internal capsule go through its anterior end giving it a striated appearance).

It is the death of the dopamine containing neurons in the substantial nigra which cause Parkinsonism. They project some of their axons to the striatum. The striatum gets input elsewhere (from the cortex using glutamic acid) and from neurons intrinsic to itself (some of which use acetyl choline as their neurotransmitter — these are called cholinergic interneurons).

The paper makes the claim that the dopamine neurons projecting to the striatum also contain the inhibitory neurotransmitter GABA.

The paper also says that the cholinergic interneurons cause release of GABA by the dopamine neurons — they bind to a type of acetyl choline receptor called nicotinic (similar but not identical to the nicotinic receptors which allow our muscles to contract) in the presynaptic terminals of the dopamine neurons of the substantial nigra residing in the striatum. Isn’t medicine and neuroanatomy a festival of terms? It’s why you need a good memory to survive medical school.

These used optogenetics (something I don’t have time to explain — but see http://en.wikipedia.org/wiki/Optogenetics ) to selectively stimulate the 1 – 2% of striatal neurons which use acetyl choline as a neurotransmitter. What they found was that only GABA (and not dopamine) was released by the dopamine neurons in response to stimulating this small subset of neurons. Even more amazing, the GABA release occurred without an action potential depolarizing the presynaptic terminal.

This literally stands everything I thought I knew about neurotransmission on its ear. How widespread this phenomenon actually is, isn’t known at this point. Clearly, the work needs to be replicated — extreme claims require extreme evidence.

Unfortunately I’ve never provided much background on neurotransmission for the hapless chemists and medicinal chemists reading this (if there are any), but medicinal chemists must at least have a smattering of knowledge about this, since neurotransmission is involved in how large classes of CNS active drugs work — antidepressants, antipsychotics, anticonvulsants, migraine therapy. There is some background on this here — https://luysii.wordpress.com/2010/08/29/some-basic-pharmacology-for-the-college-student/