John Hemming's Web Log

I tend to ask chatGPT for a summary of the transcript of videos so that I don't have to spend the time watching them. I have done this for the ALS Scientific Advisory Council from about a month ago which follows (the critique is of chatGPT - my critique is that they don't talk about mitochondria, the closest they come to epigenetics is DNA methylation): International Alliance of ALS/MND Associations Scientific Advisory Council Webinar – Transcript Summary Opening & Housekeeping Jessica Mabe (Programs Coordinator, International Alliance) welcomed attendees and introduced the webinar, noting caption availability (via Zoom chat or QR code) and thanking sponsor Mitsubishi Tanabe Pharma . The Scientific Advisory Council Chair & Moderator: Dr Nicholas Cole (Head of Research, MND Association, UK) Panelists: Dr Kuldip Dave – Vice President of Research, ALS Association (USA) Dr Nadia Sethi – Co‑chair, NE...

I think it is useful to try to identify: a) The most heavily energy using neurons b) The balance in those cells between OxPhos (which produces Reactive Oxygen Species - ROS) and Glycolysis I will be using various LLMs to search for information relating to this and will be spending time checking the responses for hallucinations, but I may not at the time of you reading this page finished validating everything. I will also be concentrating on validating the analysis for dopaminergic and motor neurons because those are the neurons which cause PD and ALS/MND. In principle the rank is not really valid. Although this table is produced using a ranking that is not going to be reliable, it is still useful. What I am trying to get from this is to identify the cells which would be vulnerable to rapid deterioration through ROS. The first step is those with a high energy usage. This, however, I would expect to vary from time to time and any actual accurate calculation for one human being ...

Regular readers of my blog will have seen that I think there is solid evidence that some neurodegenerative diseases such as ALS (MND) and Parkinsons are caused by a deterioration of mitochondrial DNA primarily because of damage by free radicals (Reactive Oxygen Species - ROS) in the cells. This gradually causes the cells to fail to produce the right proteins and the cells stop working. I think the reason this happens in ALS (MND) and Parkinson's disease is that the cells that suffer are ones which both have a high energy demand, but also make high use of Oxidative Phosphorylation (OxPhos). Hence the mitochondria generate damaging molecules at higher rate which damages the mitochondria at a higher rate than normal. Cells have systems to deal with this, but once it gets to a certain point the deterioration becomes more rapid. Cells in the Central Nervous System have a supply of melatonin via the CerebroSpinal Fluid (CSF) that helps to resist this, but if there is a shortage for...

Given the links between mtDNA damage, splicing, ALS (MND) and PD, an obvious thing to look at is Multiple Sclerosis. MS is a failure of the myelin sheaf. It has been thought to be as a result of an auto-immnue response, but an alternative perspective would be a failure of homeostasis. I thought I would ask chatGPT to look at both sides of the argument about splicing and this is the response: chatGPT O3 response to question: " what are the arguments for and against multiple sclerosis resulting from aberrant splicing in the production of myelin " The summary result from chatGPT is: Bottom line The case for aberrant splicing in myelin production as a contributor to MS is biologically plausible and experimentally supported, but the case against it being the primary cause remains strong. At present, the weight of population genetics and virology favours a model in which immune dysregulation (often EBV-driven) comes first, with myelin-splice errors acti...

Obviously when mtDNA is damaged in neurons that can have various effects depending on the damage. A key point, however, is that if there is a process which is damaging mtDNA then if that continues then the mtDNA will get further damaged. As some relatively minor damage appears to be caused by the replication of mtDNA itself then it is like there is a very slow moving footpath moving towards cell failure. Hence when looking at how to rectify this then certain points need to be made. When mtDNA is damaged this will not immediately affect the structure of the cell. What it does is to change how the cell produces or fails to produce proteins in the future. Hence if the process of mtDNA damage stops, the cell is unlikely to be in its stable state and can be expected to deteriorate in function to a point at which homeostasis is achieved. It is hard, but possible, to improve mtDNA. However, that will not immediately improve the function of the cell and it may need a stimulus to rege...

I aim to write this blog so that people don't need a detailed understanding of genetics to read it. I assume people know that genetics involves DNA being used to produce proteins. DNA is comprised of four nucleotides. Two of these are purines Adenine (A) and Guanine (G). The other two are pyrimidines Thymine (T) and Cytosine (C). They pair in two pairs A to T and G to C. Each pair is called a base pair. To produce a protein they are copied to mRNA (messenger RNA) which is then used by the ribosome to create proteins. There is DNA in the nucleus of the cell and there is also DNA in the mitochondria (the little chemical factories that generate ATP and other molecules used by the cell). There is a three base pair code (identifying which amino acid to use) used to convert DNA into protein (via mRNA). Interestingly the code is slightly different in the nucleus/ribosome to the mitochondria. So far so good. DNA can be mutated where one nucleotide for some reason or other is ch...

I wrote previously about how babies are born young. The essence is that for youth you need efficient mitochondria with a high membrane potential (when running in a steady state generating ATP). When an egg is created it is created with a mitochondrial bottleneck. This reduces the variation in mitochondrial DNA (mtDNA) to about 3 copies (according to recent research). However, this does not as far as research indicates select for better mtDNA (and hence more efficient mitochondria). Relatively few babies are born with mitochondrial disease because the eggs don't get fertilised, don't start replicating, don't implant into the uterine wall or miscarry. This is not the only reason for non-viability, but it is a reason. This is seen in how older eggs tend to be less viable. However, there is another selection process for eggs which is called "Follicular Atresia". Follicular Atresia is a really interesting process and the Wikipedia article that I link to does ...

In Parkinson’s disease, dopaminergic neurons (primarily those in the substantia nigra pars compacta) undergo progressive dysfunction and death. In amyotrophic lateral sclerosis (ALS aka MND in the UK), both upper and lower motor neurons progressively degenerate. The cells deteriorate in different ways. However, the nub of both of theses diseases is the deterioration of a particular type of neuron. An interesting question is what it is about these neurons that makes them vulnerable to rapid deterioration. Neurons are high energy cells. Dopaminergic neurons have to maintain a massive network of axons linking them to other cells. Similarly motor neurons need to maintain long axons of possibly 1 metre in length. All of this takes energy. However, what distinguishes these two types of cells is that they rely to a greater extent on Oxidative Phosphorylation (that is using the Krebs cycle to produce energy) than other neurons. OxPhos, has the effect of generating more free radical...

ALS (Amyotrophic Lateral Sclerosis) tends to be called MND (Motor Neuron Disease) in the UK. It is also known as Lou Gehrig's disease because he was a famous baseball player whose career was ended when he died of ALS in his 30s. There are perhaps two main versions of ALS Familial (or inherited) and Sporadic which does not appear to be inherited. MND is perhaps a broader category which includes Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS) and Progressive Bulbar Palsy (PBP) as well as ALS. In this post I am going to concentrate on ALS. That is not to say that things I say in this post do not necessarily also apply to the other types of MND, but I have not looked at that question as yet. I wrote a post a few weeks ago What causes Parkinson's Disease - is it actually an accelerated form of brain aging? and since then have been doing some experimentation with a small number of biohackers who have Parkinsons Disease. The hypothesis is basically that th...

An interesting paper was published recently. Intracellular metabolic gradients dictate dependence on exogenous pyruvate This was from the same lab as the excellent paper A non-canonical tricarboxylic acid cycle underlies cellular identity . An interesting question that the paper answers is what drives the need for external pyruvate. The paper concludes "The requirement for pyruvate over lactate can be partially rescued by NAD+, suggesting that at least part of the role of pyruvate in development is regulation of cellular redox62. ". What I find particularly interesting about the link to NAD+ is that Complex 1 (which is reduced in stem cells) has a major role in maintaining NAD+ levels. Hence if it is to be inhibited in some form then something else needs to be done to maintain NAD+ levels. Although Complex 1 maintains mitochondrial NAD+ rather than cytosolic NAD+, depletion in the Mitochondria will block the Malate-Aspartate shuttle affecting the cytosol Pyruvate in th...

Recently another paper was produced which hinted at a link between mitochondrial DNA damage and aging. In fact I have been of the view for some time that the damage to mitochondrial DNA is what drives both aging and development at the lowest level. I have said this before, but thought a summary would be useful. It is worth, however, explaining a few terms first before going into the details of how this happens. It is well known that animals (including people) are made of large number of cells. Within those cells there are little "organelles" called mitochondria that are used to convert nutrients into ATP (Adenosine Tri Phosphate) which is used by cells as a form of energy. There is a hypothesis that is generally believed to be true that this structure of cells arose from some bacteria going into old cells called archea as it created a form of symbiosis where the larger cells provided nutrients to the bacteria for the bacteria to process those. This is called Endosymbio...

The idea that Parkinson's Disease (PD) is an accelerated form of brain aging has been around for quite a long time. However, as with aging more generally any hypothesis as to the mechanisms behind Parkinson's needs to explain all the known research data. I have been discussing PD with a number of people over the past few months. The results from research indicate that Parkinsons is not primarily caused by genetic factors. That is because there are studies where individual twins get Parkinsons, whilst their twin does not. I was wondering, therefore, what might be an alternative cause. This paper is one that substantiates the argument that normally the brain does not age as fast as the rest of the body. What we need to look at is what might cause this to happen. If we start with the assumption from my previous posts that aging results from the mutation of mitochondrial DNA (mtDNA) then we need to find something that prevents the mutation of mtDNA in the brain that does n...