A detailed presentation of my hypothesis is given in Reviews in the Neurosciences. The title of the paper is Treatment-resistant schizophrenia: focus on the transsulfuration pathway. The abstract is below. Treatment-resistant schizophrenia: focus on the transsulfuration pathway can be viewed on ResearchGate. Ahmed A. Moustafa has been of terrific assistance in getting the hypothesis into publishable form.
Treatment-resistant schizophrenia: focus on the transsulfuration pathway
Ahmed A. Moustafa
Published Online: 2019-11-12 | DOI: https://doi.org/10.1515/revneuro-2019-0057
Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H2S) levels are low in schizophrenia. H2S is synthesized by cystathionine β-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.
I think the transsulfuration pathway could be dysregulated is other illnesses, for example, Alzheimer’s disease. I also published a paper on Alzheimer’s disease and the transsulfuration pathway. The abstract is given below. The treatment for Alzheimer’s disease and schizophrenia would be the same, which is surprising, but both diseases arise from dysregulations of the transsulfuration pathway though there are different epigenetic changes in the two diseases. My paper was published in Reviews in Neuroscience as A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway can be found on ResearchGate. Ahmed A. Moustafa has been of terrific assistance in getting the hypothesis into publishable form.
A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway
Ahmed A. Moustafa
Published Online: 2019-11-21 | DOI: https://doi.org/10.1515/revneuro-2019-0076
High homocysteine levels in Alzheimer’s disease (AD) result from low activity of the trans-sulfuration pathway. Glutathione levels are also low in AD. L-cysteine is required for the synthesis of glutathione. The synthesis of coenzyme A (CoA) requires L-cysteine, which is synthesized via the trans-sulfuration pathway. CoA is required for the synthesis of acetylcholine and appropriate cholinergic neurotransmission. L-cysteine is required for the synthesis of molybdenum-containing proteins. Sulfite oxidase (SUOX), which is a molybdenum-containing protein, could be dysregulated in AD. SUOX detoxifies the sulfites. Glutaminergic neurotransmission could be dysregulated in AD due to low levels of SUOX and high levels of sulfites. L-cysteine provides sulfur for iron-sulfur clusters. Oxidative phosphorylation (OXPHOS) is heavily dependent on iron-sulfur proteins. The decrease in OXPHOS seen in AD could be due to dysregulations of the trans-sulfuration pathway. There is a decrease in aconitase 1 (ACO1) in AD. ACO1 is an iron-sulfur enzyme in the citric acid cycle that upon loss of an iron-sulfur cluster converts to iron regulatory protein 1 (IRP1). With the dysregulation of iron-sulfur cluster formation ACO1 will convert to IRP1 which will decrease the 2-oxglutarate synthesis dysregulating the citric acid cycle and also dysregulating iron metabolism. Selenomethionine is also metabolized by the trans-sulfuration pathway. With the low activity of the trans-sulfuration pathway in AD selenoproteins will be dysregulated in AD. Dysregulation of selenoproteins could lead to oxidant stress in AD. In this article, we propose a novel treatment for AD that addresses dysregulations resulting from low activity of the trans-sulfuration pathway and low L-cysteine.
I have lots of very sound ideas on how the mental health system could be improved and lots of very justified complaints about how the current mental health system is run but views of individuals on the mental health system are entrenched. If I expressed my very sound views on how the mental health system could be improved or expressed my very justified complaints about the mental health system I would effectively only be ranting. This blog is going to be narrowly focused on the biological basis of schizophrenia and other neurological illnesses such as Alzheimer’s disease.
I have a science fiction novel, Republic of Helios, that can purchased on Smashwords and on other E-book outlets.
In Republic of Helios Richard Thorne has invented a device that can teleport objects. The devices, called Topoi, can be easily and inexpensively constructed. With Topoi devices transportation costs are almost nil. There is a catch. If there are no receiving Topoi at destinations objects when teleported explode at destinations. Topoi could be used as WMD letting lone wolves destroy nations taking Earth back to the Paleolithic. Topoi could also be used to open the solar system to human habitation and colonies. Topoi could be used to terraform Mars in decades rather than millennia. Richard is determined to keep Topoi tech under tight control, however, he is also determined to terraform Mars. To fund operations Richard sets up Helios Transportation to teleport satellites to Earth orbit. The first step is setting up a station on the Moon where employees of Helios Transportation cannot be attacked.
Besides opening Mars to human habitation Richard is setting up a new nation, with a new enhanced government, the Republic of Helios. Republic of Helios is Book 1 of The Anti-Apocalypse Trilogy. Republic of Helios is a novel of ideas as well as exploration and adventure in space. in Republic of Helios the Earth is seen as being led to catastrophe by Spinozists who act esoterically. In Spinoza’s view, individuals have a natural right to everything that he or she desires and he or she can obtain. For Spinoza an individual’s right is equivalent to his or her power. Spinoza also held that those who can deceive have the right to deceive. In the Republic of Helios Spinozists closely follow Spinoza on power, right and deception. Spinozists seek to maintain facades of gentility while working to undermine the West. All that has to be accepted in the Republic of Helios is teleportation devices have been invented and that the words of Spinoza show how Spinozists act. All else follows logically.
At one time I was correctly diagnosed as having schizophrenia. A diagnosis of schizophrenia would not fit now.
The graphic at the top of the website pages shows methylation marks (shiny spots) on DNA. Methylation marks placed on genes control transcription of genes. I think epigenetic changes in schizophrenia and Alzheimer’s disease can lead to the development of schizophrenia and Alzheimer’s disease.