Tag Archives: schizophrenia

Biological mechanisms of generalised brain disease such as Alzheimer’s disease and schizophrenia

In a previous post, I discussed a theory concerning the causes of chronic brain diseases. This invoked the idea that the brain accumulated deleterious gene rearrangements during periods of rapid growth and remoulding, particularly those taking place at around 20 weeks of gestational age. The rate of mutation is enhanced by the action of reverse transcriptase that is heavily expressed during this period of neuronal division and synaptic pruning. The idea was that these somatic mutations might be propagated and increase the risk of diseases such as schizophrenia.

There was, however, a problem with the theory. How could a defect in one clone of neurones result in such a pervasive brain condition as schizophrenia or dementia? A possible mechanism is coming to light through the work of neuroanatomists who are using functional imaging on a massive scale to track previously invisible brain networks. This subject of ‘connectomics’ uncovers the networks through which disease may actually spread through the brain. It seems that the neurone malfunction can spread through the brain a little like a virus and perhaps the clue will come from the behaviour of infectious proteins such as those responsible for the spread of encephalopathies.1 We shall see!

1.    Zhou J, Gennatas DE, Kramer JH, Miller BL, Seely WW. Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome. Neuron. 2012; 73:1226-1227

An hypothesis on the cause of many chronic neurological conditions, such as schizophrenia and Alzheimer’s disease.

My blog normally concerns ethics, politics, policy and clinical research. However, I do not subscribe to the two cultures ethos, so this week is something different.

The discovery of gene-imprinting changed the world-view of genetics radically. It provided an important mechanism for non-Mendelian inheritance; it explained a number of paradoxes, such as the generational lag between improvement in nutrition and change in mean height of the population; and it also explained how inheritance of a defective gene could yield a completely different phenotype according to whether it was inherited from the mother or father. However, this important discovery might be eclipsed in importance by the discovery of the extent to which genes are turned on and off – not by imprinting, but by lincRNAs (Large Intergenic Non-Coding RNAs). The ENCODE programme (Encyclopedia Of DNA Elements) (http://www.nature.com/encode/) showed that this phenomenon was more important than originally thought. Many of the lincRNAs that jump around the genome regulating gene activity originated from viral sequences that inserted themselves in DNA way back in evolution.[1]

My colleague, David Miller, and I discovered large amount of LINE1-derived RNA coding reverse transcriptase in sperm.[2,3] Such genes can perpetuate themselves within the genome. We hypothesised that this RNA was left over from progenitor stages of the zygote, and that this, like imprinting, would provide a mechanism to accelerate the process of evolution. Such large scale “natural experiments,” we postulated, could lead to radical genetic, and hence phenotypic, changes over the rapid time course of human evolution over a breathless one million years or so.

It turns out that reverse transcriptase is also very highly expressed in foetal neurons over the period of rapid brain remodelling that takes place at about 20 weeks gestational age.[4] At this stage of development neurons first divide rapidly to reach a total of 100 billion before being pruned down to about 10 billion, which will persist into adult life. Further stages of brain remodelling take place at about two years of age and following puberty. Some time back I hypothesised that some neuro-psychiatric diseases have origins arising during these ‘vulnerable’ periods of neurodevelopment, during which rapid reorganisation of the genome takes place. Too late, I had not started blogging in those days, and now the hypothesis is quite mainstream.

Many conditions (such as schizophrenia and depressive psychosis) have enigmatic origins. They have a genetic element and environmental factors play a part. Yet concordance for schizophrenia among identical twins is less than 50% [5] despite shared genes and environment. Of course identical twins have dissimilar intra-uterine environment, and this could explain discordance. However, the above hypothesis invokes a stochastic element linked to ‘jumping genes’ during periods of brain remodelling. Some genetic rearrangements are likely to be lethal to affected cells, some anodyne and yet others may have effects on gene function. Changes in only a small proportion of neurons may be magnified during the neuro-proliferative phase and predispose to the long-term phenotype, interacting with inherited genetic traits and environmental factors. If this is so, then some elements on the causative chain may take on features of a chaotic system in the sense that a wide variety of individually undetectable changes may be magnified through their interaction with other events to determine the outcome in question. To put this another way, it may be difficult to prove the hypothesis, but molecular studies seem to indicate it is at least plausible. I would never have thought that evolution could produce such a variegated system of inheritance – an example of unintelligent design?

[1] RNA-only genes. The origin of species? The Economist. 2012 (Dec 1): 87-88.
[2] Miller D, Tang PZ, Skinner C, Lilford R. Differential RNA fingerprinting as a tool in the analysis of spermatozoal gene expression. Hum Reprod. 1994; 9(5):864-9.
[3] Miller D, Briggs D, Snowden H, Hamlington J, Rollinson S, Lilford R, Krawetz SA. A complex population of RNAs exists in human ejaculate spermatozoa: implications for understanding molecular aspects of spermiogenesis. Gene. 1999; 237(2):385-92.
[4] Abrusán G. Somatic transposition in the brain has the potential to influence the biosynthesis of metabolites involved in Parkinson’s disease and schizophrenia. Biol Direct. 2012; 7: 41.
[5] Noll R. The Encyclopedia of Schizophrenia and Other Psychotic Disorders. Third Edition. New York, NY: Infobase Publishing. p.104