Tag Archives: Parkinsonism

First Debate — What did the neurologist think?

As my brother sometimes says “everyone is entitled to my opinion”.  Why should you be interested in mine?  Because I was a clinical neurologist from 1968 to 2000 seeing probably 25,000 patients over the years. Because I was board certified by the American Board of Psychiatry and Neurology.  Because later I examined candidates for certification for the same board.  Because I have an extensive experience with dementia in patients, and (unfortunately) with close friends and their kin and in our family.

The main question I had before the debates, was “Is Joe Biden cognitively impaired”, given the selection of his statements and gaffes.

The short answer is no.  He held his own, and moreover did so for 90 stressful minutes.

The more nuanced answer is that there are a few things about him that are not 100%.  As the time wore on, he mispronounced and slurred more words.  Also the right corner of his mouth appeared to sag a bit more (but no one has a perfectly symmetrical face).

The most unusual feature is Biden’s upper face — it doesn’t move. The masklike face is a symptom of Parkinsonism, but if so it is the only one.  I’m ashamed to admit that I didn’t notice how often his eyes blinked, but since I didn’t notice infrequent blinking (another sign of Parkinsonism) it probably wasn’t present. The prosody of his speech  (https://en.wikipedia.org/wiki/Prosody_(linguistics)) is normal, not diminished as it would be in Parkinsonism.  Is he on botox?  He has a remarkably unlined face for a man his age.

Biden often appeared to be looking down at something — talking points?  mini-teleprompter?

Is Trump impaired cognitively?  No sign of it.  His responses were quick, sometimes funny and often not to the point.   Both men are smart, but Trump appears (to me) to be smarter.

Although Chris Wallace is from Fox News hence suspect for many,  I thought he was a tough and impartial moderator, which is exactly what I wanted.

I did look at a C-Span segment of the audience settling down before the actual debate and was horrified.  50% not wearing masks, people shaking hands, getting far closer than 6 feet from each other.   Even if they’d all been recently tested for the virus, this was irresponsible behavior and an extremely poor model for the country.

How flat can a 100 amino acid protein be?

Alpha-synuclein is of interest to the neurologist because several mutations cause Parkinson’s disease or Lewy Body dementia.  The protein accumulates in the Lewy Bodies of these diseases.  These are concentric hyaline inclusions over 15 microns in diameter found in pigmented brain stem nuclei (substantia nigra, locus coeruleus).

The protein contains 140 amino acids.  It is ‘natively unfolded’ meaning that it has no ordered secondary structure (alpha helix, beta sheet).  No one is sure what it does.  Mouse knockouts are normal, so the mutations must produce something new.

Alpha-synuclein can form amyloid fibrils, which are basically stacks of pancakes made of flattened segments of proteins one on top of the other.

Would you believe that the 100 amino terminal amino acids of alpha-synuclein can form an absolutely flat structure.  Well it does and there are pictures to prove it in PNAS vol. 117 pp. 20305 – 20315 ’20.  Here’s a link if you or your institution has a subscription — https://www.pnas.org/content/pnas/117/33/20305.full.pdf.

This isn’t the usual alpha-synuclein, as it was chemically synthesized with phosphorylated tyrosine at amino acid #39.  Who would have ever predicted that 100 amino acids could form a structure like this?  I wouldn’t. The structure was determined by cryoEM and all the work was done in China.  Very state of the art world class work.  Bravo.

Has the holy grail for Parkinson’s disease been found?

Will the horribly named SynuClean-D treat Parkinsonism?  Here is the structure described  verbally.  Start with pyridine.  In the 2 position put benzene with a nitrogroup in the meta position, position 3 on pyridine NO2, position 4 CF3, position 5 CN (is this trouble?) position 6 OH.  That’s it.  Being great chemists you can immediately see what it does.

Back up a bit.  One of the pathologic findings in parkinsonism in the 450,000 dopamine neurons we have in the pars compacta at birth, is the Lewy body, which is largely made of the alpha-synuclein protein.  This is thought to kill the neurons in some way (just which form of alpha-synuclein is the culprit is still under debate — the monomer, the tetramer etc. etc).  Even the actual conformation of the monomer is still under debate (intrinsically disordered) etc. etc.

The following paper [ Proc. Natl. Acad. Sci. vo. 115 pp. 10481 – 10486 ’18 ] claims that SynuClean-D inhibits alpha-synuclein aggregation, disrupts mature amyloid fibrils made from it, prevents fibril propagation and abolishes the degeneration of dopamine neurons in an animal model of Parkinsonism.  Wow ! ! !

Time for some replication — look at the disaster from Harvard Med School about cardiac stem cells, with 30+ papers retracted. https://www.nytimes.com/2018/10/15/health/piero-anversa-fraud-retractions.html.  Ghastly.

A pile of spent bullets — take II

I can tell you after being in neurology for 50 years that back in the day every microscopic inclusion found in neurologic disease was thought to be causative.  This was certainly true for the senile plaque of Alzheimer’s disease and the Lewy body of Parkinsonism.  Interestingly, the protein inclusions in ALS weren’t noticed for decades.

However there are 3 possible explanations for any microscopic change seen in any disease.  The first is that they are causative (the initial assumption).  The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer.  The third is they are tombstones, the final emanations of a dying cell, a marker for the cause of death rather than the cause itself.

An earlier post concerned work that implied that the visible aggregates of alpha-synuclein in Parkinson’s disease were protective rather than destructive — https://luysii.wordpress.com/2018/01/07/are-the-inclusions-found-in-neurologic-disease-attempts-at-defense-rather-then-the-cause/.

Comes now Proc. Natl. Acad. Sci. vol. 115 pp. 4661 – 4665 ’18 on Superoxide Dismutase 1 (SOD1) and ALS. Familial ALS is fortunately less common than the sporadic form (under 10% in my experience).  Mutations in SOD1 are found in the familial form.  The protein contains 153 amino acids, and as 6/16 160 different mutations in SOD1 have been found.  Since each codon can contain only 3 mutations from the wild type, this implies that, at a minimum,  53/153 codons of the protein have been mutated causing the disease.  Sadly, there is no general agreement on what the mutations actually do — impair SOD1 function, produce a new SOD1 function, cause SOD1 to bind to something else modifying that function etc. etc.  A search on Google Scholar for SOD1 and ALS produced 28,000 hits.

SOD1 exists as a soluble trimer of proteins or the fibrillar aggregate.   Knowing the structure of the trimer, the authors produced mutants which stabilized the trimer (Glycine 147 –> Proline) making aggregate formation less likely and two mutations (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine) which destabilized the trimer making aggregate formation more likely.  Then they threw the various mutant proteins at neuroblastoma cells and looked for toxicity.

The trimer stabilizing mutant  (Glycine 147 –> Proline) was toxic and the destabilizing mutants  (Asparagine 53 –> Isoleucine, and Aspartic acid 101 –> Isoleucine)  actually improved survival of the cells.  The trimer stabilizing mutant was actually more toxic to the cells than two naturally occurring SOD1 mutants which cause ALS in people (Alanine 4 –> Valine, Glycine 93 –> Alanine).  Clearly with these two something steric is going on.

So, in this experimental system at least, the aggregate is protective and what you can’t see (microscopically) is what kills cells.

Paul Schleyer 1930 – 2014, A remembrance

Thanks Peter for your stories and thoughts about Dr. Schleyer (I never had the temerity to even think of him as Paul). Hopefully budding chemists will read it, so they realize that even department chairs and full profs were once cowed undergraduates.

He was a marvelous undergraduate advisor, only 7 years out from his own Princeton degree when we first came in contact with him and a formidable physical and intellectual presence even then. His favorite opera recording, which he somehow found a way to get into the lab, was don Giovanni’s scream as he realized he was to descend into Hell. I never had the courage to ask him if the scars on his face were from dueling.

We’d work late in the lab, then go out for pizza. In later years, I ran into a few Merck chemists who found him a marvelous consultant. However, back in the 50’s, we’d be working late, and he’d make some crack about industrial chemists being at home while we were working, the high point of their day being mowing their lawn.

I particularly enjoyed reading his papers when they came out in Science. To my mind he finally settled things about the nonclassical nature of the norbornyl cation — here it is, with the crusher being the very long C – C bond lengths

Science vol. 341 pp. 62 – 64 ’13 contains a truly definitive answer (hopefully) along with a lot of historical background should you be interested. An Xray crystallographic structure of a norbornyl cation (complexed with a Al2Br7- anion) at 40 Kelvin shows symmetrical disposition of the 3 carbons of the nonclassical cation. It was tricky, because the cation is so symmetric that it rotates within crystals at higher temperatures. The bond lengths between the 3 carbons are 1.78 to 1.83 Angstroms — far longer than the classic length of 1.54 Angstroms of a C – C single bond.

I earlier wrote a post on why I don’t read novels, the coincidences being so extreme that if you put them in a novel, no one would believe them and throw away the book — it involves the Princeton chemistry department and my later field of neurology — here’s the link https://luysii.wordpress.com/2014/11/13/its-why-i-dont-read-novels/

Here’s yet another. Who would have thought, that years later I’d be using a molecule Paul had synthesized to treat Parkinson’s disease as a neurologist. He did an incredibly elegant synthesis of adamantane using only the product of a Diels Alder reaction, hydrogenating it with a palladium catalyst and adding AlCl3. An amazing synthesis and an amazing coincidence.

As Peter noted, he was an extremely productive chemist and theoretician. He should have been elected to the National Academy of Sciences, but never was. It has been speculated that his wars with H. C. Brown made him some powerful enemies. I’ve heard through the grapevine that it rankled him greatly. But virtue is its own reward, and he had plenty of that.

R. I. P. Dr. Schleyer