John Hemming's Web Log

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...