Tag Archives: Parkinsonism

A totally unsuspected information processing mechanism in the brain

This is pretty hard core stuff for the neurophysiology, neuropharmacology and  neuroscience cognoscenti.  You can skip it if you’re satisfied with our understanding of how the brain works, and our current treatments for neurological and psychiatric disease.  You aren’t?  Join the club and read on.

We thought we pretty much understood axons.  They were wires conducting nerve impulses (action potentials) from the cell body to their far away ends, where the nerve impulses released neurotransmitters which then affected other neurons they were connected to by synapses.

We knew that there were two places on the axon where receptors for neurotransmitters were found, allowing other neurons to control what the axon did.  The first was the place where axon leaves the cell body, called the axon initial segment (AIS).  Some of them are controlled by the ends of chandelier cells — interneurons with elaborate specialized synapses called cartridges.   The second was on the axon terminals at the synapse — the presynapse.  Receptors for the transmitter to be released were found (autoreceptors) and for other neurotransmitters (such as the endocannabinoids (( our indigenous marihuana)) released by the presynaptic cell.

Enter a blockbuster paper from Science (volume 375 pp. 1378 – 1385 ’22) science.abn0532-2.pdf.  It shows (in one particular case) that the axons themselves have receptors for a particular transmitter (acetyl choline) which partly can control their behavior.  I sure people will start looking for this elsewhere. The case studied is of particular interest to the neurologist, because the axons are from dopamine releasing neurons in the striatum.  Death of these neurons causes parkinsonism.

The work used all sort of high technology including G Protein Coupled Receptors (GPCRs) highly modified so that when dopamine hit them a fluorescent compound attached to them lit up, permitting the local concentration of dopamine to be measured in the living brain.  Another such GPCR was used to measure local acetyl choline concentration.

The dopamine axons contain a nicotinic type receptor for acetyl choline.  Stimulation of the interneurons releasing acetyl choline caused a much larger release of dopamine (in an area estimated to contain 3 to 15 million dopamine axon terminals.  The area covered by dopamine release was 3 times larger than the area covered by acetyl choline release, implying that the acetyl choline was causing the axons to fire.

The cell body of the dopamine neuron had nothing to do with it, as the phenomenon was seen in brain slices of the striatum (which have no input from the dopamine cell bodies.

They could actually study all this in living animals, and unsurprisingly, there were effects on movement with increased striatal dopamine and acetyl choline being associated with movement of the animal to the opposite side.

So this is an entirely novel mechanism for the control of neural activity.  How widespread such a mechanism is awaits further study, as is whether it is affected in various diseases, and whether manipulation of it will do any good (or harm).

Exciting times.



We now understand what amyloid actually is

Lately we have received an embarrassment of riches about amyloid and the diseases it causes.  I’ll start with the latest — the structure of TDP amyloid.

I must say it is a pleasure to get back to chemistry and away from the pandemic, however briefly.  So relax and prepare to enjoy some great chemistry and protein structure.

TDP43 (you don’t to know what the acronym stands for) is a protein which binds to RNA (among other things).  It also forms aggregates, and some 50 mutations are known producing FrontoTemporal  Dementia (FTD) and/or Amyotrophic Lateral Dementia (ALS).  I saw a case as a resident (before things were worked out) and knew something was screwy because while ALS is a horrible disease, patients are clear to the end (witness Stephen Hawking) and my patient was clearly dementing.

Mutations in TDP43 occur in 5% of familial ALS.  More to the point cytoplasmic aggregates of TDP43 occur in 95% of sporadic cases of ALS (no mutations), so neurologists have been fascinated with TDP43 for years.

Back before we knew much about the structure of amyloid, it was characterized by the dyes that would bind to it (Congo Red, thioflavin etc.) and birefringence (see below).  None of this is true for the aggregates of TDP43.

Well we now know what the structure of amyloid is.  You simply can’t do better than  Cell vol. 184 pp. 4857 – 4873 ’21 — but it might be behind a paywall.

So here’s the skinny about what amyloid actually is —


It is a significantly long polypeptide chain  flattening  out into a 4.8 Angstrom thick sheet, essentially living in 2 dimensions.  Thousands of sheets then pile on top of each other forming amyloid.  So amyloid is not a particular protein, but a type of conformation a protein can assume (like the alpha helices, beta pleated sheets etc. etc. ).

The structure also explained why planar molecules like Congo Red bind to amyloid (it slips between the sheets).   Or at least that’s what I thought.


Enter Nature vol. 601 pp. 29 – 30, 139 – 143 ’22 showing that some 79 amino acids of the 414 amino acids of TDP43 flatten out into single sheet in the aggregates, with the sheets piling on top of each other.  If that isn’t amyloid, what is?


Where are the beta strands producing birefringence if this is amyloid.  In fact where is the birefringence? (see below). The paper says that there are 10 beta strands in the 79 amino acids, but they are short with only two of them containing more than 3 amino acids (I guess they can see beta strands by measuring backbone angles a la Ramachandran plots).  The high number of glycine mediated turns prevents beta sheets from stacking next to each other precluding the crossBeta  structure (and birefringence).


Why doesn’t Congo Red bind?  My idea about how it binds to other amyloids (slipping between the sheets) clearly is incorrect.


There are all sorts of fascinating points about the amyloid of TDP43.  The filaments derived from patients are stable to heating to 65 C.   The structure of the TDP43 fibrils derived from patients with FTD/ALS are quite different in structure from synthetic filaments made from parts of TDP43, so possibly a lot of work will have to be done again.


Here is some more detail on amyloid structure:


So start with NH – CO – CHR.  NH  CO and C in the structure all lie in the same plane (the H and the side chain of the amino acid < R >  project out of the plane).
Here’s a bit of elaboration for those of you whose organic chemistry is a distant memory.  The carbon in the carbonyl bond (CO) has 3 bonding orbitals in one plane 120 degrees apart, with the 4th orbital perpendicular to the plane — this is called sp2 hybridization.  The nitrogen can also be hybridized to sp2.  This lets the pair of electrons above the plane roam around moving toward the carbon.  Why is this good?  Because any time you let electrons roam around you increase their entropy (S) and anything increasing entropy lowers their free energy (F)which is given by the formula F = H – TS where H is enthalpy (a measure of bond strength, and T is the absolute temperature in Kelvin.


So N and CO are in one plane, and so are the bonds from  N and C to the adacent atoms (C in both cases).


You can fit the plane atoms into a  rectangle 4.8 Angstroms high.  Well that’s one 2 dimensional rectangle, but the peptide bond between NH and CO in adjacent rectangles allows you to tack NH – CO – C s together while keeping them in a 3 dimensional parallelopiped 4.8 Angstroms high


Notice that in the rectangle the NH and CO bonds are projecting toward the top and bottom of the rectangle, which means that in each plane  NH – CO – CHR s, the NH and CO are pointing out of the 2 dimensional plane (and in opposite directions to boot). This is unlike protein structure in which the backbone NHs and COs hydrogen bond to each other.  There is nothing in this structure for them to bond to


What they do is hydrogen bond to another 3 dimensional parallelopiped (call it a sheet, but keep in mind that this is NOT the beta sheet you know about from the 3 dimensional structures of proteins we’ve had for years).
So thousands of sheets stacked together form the amyloid fibril.


Where does the 9 Angstrom reflection of cross beta (and birefringence) come from?  Consider the  [ NH – CHR – CO ]  backbone as it lies in the 4.8  thick plane (Having studied proteins structure since entering med school in ’62, I never thought such a thing would even be possible ! ).  It curves around like a snake lying flat.  Where are the side chains?  They are in the 4.8 thick plane, separating parts of the meandering backbone from each other — by an average of 9 Angstroms.
Here is an excellent picture of the Alzheimer culprit — the aBeta42 peptide as it forms the amyloid of the senile plaque
You can see the meandering backbone and the side chains keeping the backbone apart.

Then Nature [ vol. 598,  pp. 359 – 363 ’21] blows the field wide open, finding 19 different conformations of tau in clinically distinct diseases. Each clinical disease appears to be associated with a distinct polymorphism.  This is also true for the polymorphisms of alpha-synuclein, with distinct conformations being seen in each of Parkinsonism, multiple system atrophy and Lewy body dementia.

In none of the above diseases is there a mutation (change in amino acid sequence) in the protein.

Henry J. Heinz claimed to have 57 varieties of pickles in 1896, but Cell [ vol. 184 pp. 4857 – 4873 ’21  ] Page 4862 claims that 24 amyloid polymorphs of alpha-synuclein have been found and structurally characterized.  Recall that alpha-synuclein amyloid is the principal component of the Lewy body of Parkinsonism  and Lewy Body disese

How did they get the 24 different conformations?  They incubated the protein under different conditions (e.g. different salt concentrations, different alpha-synuclein concentrations, different salts).

Why is this incredibly good news? 

Because it moves us past amyloid itself, to the conditions which cause amyloid to form.  Certainly, removing amyloid or attacking it hasn’t resulted in any clinical benefit for the Alzheimer patient despite billions being spent by Big Pharma to do so.

We will start to study the ‘root causes’ of amyloid formation.   The amino acid sequence of each protein is identical despite the different conformations of the chain in the amyloid. Clearly the causes must be different for each of the different polymorphs of the protein.  This just has to be true.

Amyloid Structure At Last ! 4 Polymorphs

Henry J. Heinz claimed to have 57 varieties of pickles in 1896, but Cell [ vol. 184 pp. 4857 – 4873 ’21  ] Page 4862 claims that 24 amyloid polymorphs of alpha-synuclein have been found and structurally characterized.

What does this actually mean in English? The previous 3 articles in this series have discussed the structure of amyloid — the most relevant being https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/

Basically, in amyloid some of the protein backbone flattens out so it lies in a single plane, and thousands of the planes stack on top of each other producing the amyloid fiber.  In the case of alpha-synuclein some 56 of the 144 amino acids comprising the protein flatten out.   Just as throwing a chain with 56 links on the floor will give different conformations of the chain,  the conformation of alpha-synuclein is different in each of the polymorphs.

So what?

Well, different polymorphs of another protein, the tau protein which forms the neurofibrillary tangle in Alzheimer’s give rise to at least 25 clinically distinct neurological diseases called tauopathies (3 more are chronic traumatic encephalopathy, corticobasal degeneration, and Pick’s disease).  In each of the these four diseases, a different conformation of tau is seen.

Then Nature [ vol. 598,  pp. 359 – 363 ’21] blows the field wide open, finding 19 different conformations of tau in clinically distinct diseases. Each clinical disease appears to be associated with a distinct polymorphism.  This is also true for the polymorphisms of alpha-synuclein, with distinct conformations being seen in each of Parkinsonism, multiple system atrophy and Lewy body dementia.

In none of the above diseases is there a mutation (change in amino acid sequence) in the protein

Back to alpha-synuclein.  How did they get the 24 different conformations?  They incubated the protein under different conditions (e.g. different salt concentrations, different alpha-synuclein concentrations, different salts).

Why is this incredibly good news? 

Because it moves us past amyloid itself, to the conditions which cause amyloid to form.  Certainly, removing amyloid or attacking it hasn’t resulted in any clinical benefit for the Alzheimer patient despite billions being spent by Big Pharma to do so.

We will start to study the ‘root causes’ of amyloid formation.   The amino acid sequence of each protein is identical despite the different conformations of the chain in the amyloid. Clearly the causes must be different for each of the different polymorphs of the protein.  This just has to be true.

Some cynic said that people who talk about the root causes of crime never get their hands dirty.  Hopefully neuroscience is about to take off its gloves.

This is why alternative approaches to Alzheimer’s disease, such as Cassava Biosciences manipulation of filamin A, might bear fruit.   For details please see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

Just got this back from one of the authors of the Nature paper

“Yes, studying the conditions that lead to all these different structures
is certainly high on our to-do list now.”


Cassava Sciences 9 month data is probably better than they realize

My own analysis of the Cassava Sciences 9 month data shows that it is probably even better than they realize.

Here is a link to what they released — keep it handy https://www.cassavasciences.com/static-files/13794384-53b3-452c-ae6c-7a09828ad389.

I was unable to listen to Lindsay Burn’s presentation at the Alzheimer Association International Conference in July as I wasn’t signed up.  I have been unable to find either a video or a transcript, so perhaps Lindsay did realize what I’m about to say.

Apparently today 25 August there was another bear attack on the company and its data.  I’ve not read it or even seen what the stock did.  In what follows I am assuming that everything they’ve said about their data is true and that their data is what they say it is.

So the other day I had a look at what Cassava released at the time of Lindsay’s talk.

First some background on their study.  It is a report on the first 50 patients who had received Simulfilam for 9 months.  It is very important to understand how they were measuring cognition.  It is something called ADAS-Cog11

Here it is and how it is scored and my source — https://www.verywellhealth.com/alzheimers-disease-assessment-scale-98625

The original version of the ADAS-Cog consists of 11 items, including:1

1. Word Recall Task: You are given three chances to recall as many words as possible from a list of 10 words that you were shown. This tests short-term memory.

2. Naming Objects and Fingers: Several real objects are shown to you, such as a flower, pencil and a comb, and you are asked to name them. You then have to state the name of each of the fingers on the hand, such as pinky, thumb, etc. This is similar to the Boston Naming Test in that it tests for naming ability, although the BNT uses pictures instead of real objects, to prompt a reply.

3. Following Commands: You are asked to follow a series of simple but sometimes multi-step directions, such as, “Make a fist” and “Place the pencil on top of the card.”

4. Constructional Praxis: This task involves showing you four different shapes, progressively more difficult such as overlapping rectangles, and then you will be asked to draw each one. Visuospatial abilities become impaired as dementia progresses and this task can help measure these skills.

5. Ideational Praxis: In this section, the test administrator asks you to pretend you have written a letter to yourself, fold it, place it in the envelope, seal the envelope, address it and demonstrate where to place the stamp. (While this task is still appropriate now, this could become less relevant as people write and send fewer letters through the mail.)

6. Orientation: Your orientation is measured by asking you what your first and last name are, the day of the week, date, month, year, season, time of day, and location. This will determine whether you are oriented x 1, 2, 3 or 4.

7. Word Recognition Task: In this section, you are asked to read and try to remember a list of twelve words. You are then presented with those words along with several other words and asked if each word is one that you saw earlier or not. This task is similar to the first task, with the exception that it measures your ability to recognize information, instead of recall it.

8. Remembering Test Directions: Your ability to remember directions without reminders or with a limited amount of reminders is assessed.

9. Spoken Language: The ability to use language to make yourself understood is evaluated throughout the duration of the test.

10. Comprehension: Your ability to understand the meaning of words and language over the course of the test is assessed by the test administrator.

11. Word-Finding Difficulty: Throughout the test, the test administrator assesses your word-finding ability throughout spontaneous conversation.

What the ADAS-Cog Assesses

The ADAS-Cog helps evaluate cognition and differentiates between normal cognitive functioning and impaired cognitive functioning. It is especially useful for determining the extent of cognitive decline and can help evaluate which stage of Alzheimer’s disease a person is in, based on his answers and score. The ADAS-Cog is often used in clinical trials because it can determine incremental improvements or declines in cognitive functioning.2


The test administrator adds up points for the errors in each task of the ADAS-Cog for a total score ranging from 0 to 70. The greater the dysfunction, the greater the score. A score of 70 represents the most severe impairment and 0 represents the least impairment.

The average score of the 50 individuals entering was 17 with a standard deviation of 8, meaning that about 2/3 of the group entering had scores of 9 to 25 and that 96% had scores of 1 to 32 (but I doubt that anyone would have entered the study with a score of 1 — so I’m assuming that the lowest score on entry was 9 and the highest was 25).  Cassava Sciences has this data but I don’t know what it is.

Now follow the link to Individual Patient Changes in ADAS-Cog (N = 50) and you will see 50 dots, some red, some yellow, some green.

Look at the 5 individuals who fall between -10 and – 15 and think about what this means.  -10 means that an individual made 10 fewer errors at 9 months than on entry into the study.  Again, I have no idea what the scores of the 5 were on entry.

So assume the worst and that the 5 all had scores of 25 on entry.  The group still showed a 50% improvement from baseline as they look like they either made 12, 13, or 14 fewer errors.  If you assume that the 5 had the average impairment of 17 on entry, they were nearly normal after 9 months of treatment.  That doesn’t happen in Alzheimer’s and is a tremendous result.   Lindsay may have pointed this out in her talk, but I don’t know although I’ve tried to find out.

Is there another neurologic disease with responses like this.  Yes there is, and I’ve seen it.

I was one of the first neurologists in the USA to use L-DOPA for Parkinsonism.  All patients improved, and I actually saw one or two wheelchair bound Parkinsonians walk again (without going to Lourdes).  They were far from normal, but ever so much better.

However,  treated mildly impaired Parkinsonians became indistinguishable from normal, to the extent that I wondered if I’d misdiagnosed them.

12 to 14 fewer errors is a big deal, an average decrease of 3 errors, not so much, but still unprecedented in Alzheimer’s disease.   Whether this is clinically meaningful is hard to tell.  However, 12 month data on the 50 will be available in the fourth quarter of ’21, and if the group as a whole continues to improve over baseline it will be a very big deal as it will tell us a lot about Alzheimer’s.

Cassava Sciences has all sorts of data we’ve not seen (not that they are hiding it).  Each of the 50 has 4 data points (entry, 3, 6 and 9 months) and it would be interesting to see the actual scores rather than the changes between them in all 50.  Were the 5 patients with the 12 – 14 fewer errors more impaired (high ADAS-Cog11 score in entry) or less.

Was the marked improvement in the 5 slow and steady or sudden?   Ditto for the ones who deteriorated or who got much worse or who slightly improved.

Even if such dramatic improvement is confined to 10% of those receiving therapy it is worth a shot to give it to all.  Immune checkpoint blockade has dramatically helped some patients with cancer  (far from all), yet it is tried in many.

Disclaimer:  My wife and I have known Lindsay since she was a teenager and we were friendly with her parents.  However, everything in this post is on the basis of public information available to anyone (and of course my decades of experience as a clinical neurologist)


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