Thiamin and protein folding

[Diokine]

By Derrick Lonsdale

Lonsdale has written over 100 published papers[3] and the conclusions tend to support the idea that healing comes from the body itself rather than from external medical interventions.[5]

Lonsdale has studied the use of nutrients to prevent diseases and his work has been favorably reviewed. [6][7] He is particularly interested in Vitamin B1, also known as thiamine. Lonsdale's research on the effect of high doses of thiamine has been described as 'pioneering'.[7]

Lonsdale led a successful (uncontrolled) study on the treatment of autism spectrum children with thiamine.

Thiamin and protein folding

A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. Proteins are made up of chains of amino acids and the folding process is exquisitely complex. When this folding process is inhibited, the respective protein is referred to as being misfolded and nonfunctional. So the hypothesis that follows is in regard to the diseases that are caused by the misfolding of vital proteins and their reported relationship with thiamin metabolism.

The physiological form (PrP C) is a cell surface glycoprotein expressed mainly in the central nervous system. Despite numerous efforts to elucidate its role, the exact biological function remains unknown. Prion-induced diseases, due to the conformational change in the protein, are a global health problem, with lack of effective therapy and 100% mortality. Thiamin and its derivatives bind the prion protein and intermolecular actions have been noted between thiamin and other thiamin-binding proteins, although the exact importance of this is conjectural.

The major neurodegenerative diseases share some common pathological features including the involvement of mitochondria in the mechanism of pathology, protein misfolding and the accumulation of abnormally aggregated proteins. All these misfolded aggregates affect mitochondrial energy metabolism by inhibiting diverse mitochondrial complexes and limit ATP availability in neurons

Mitochondrial oxidative phosphorylation is not perfectly coupled to ATP synthesis, giving rise to proton-leak that accounts for a significant part of the resting metabolic rate. Uncoupling proteins are involved. Understanding the metabolic factors that contribute to energy metabolism is critical for the development of treatment of many diseases

Impaired glucose metabolism, decreased levels of thiamin and its phosphate esters and reduced activity of thiamin-dependent enzymes occur in Alzheimer’s disease. Thiamin deficiency (TD) exacerbates amyloid beta deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine, a derivative of thiamin, together with chronic dietary treatment, increased the lifespan, improved behavior and prevented death of motor neurons in mice

Thiamin phosphorylated derivatives are associated with the specific protein forming the sodium channel, suggesting that these derivatives and more specifically thiamin triphosphate, are directly involved in the conductance change [20]. Thiamin deficiency (TD) causes regional selective neuronal loss in the brain and has been used to model neurodegeneration that accompanies mild impairment of oxidative metabolism. Although the mechanism is incompletely elucidated, TD upregulated several markers of endoplasmic reticulum stress [21]. The endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. If protein folding is not resolved by the unfolded protein response, cells die.

Considered to be surprisingly widespread, TD may be responsible for breakdown of organ systems through longstanding energy deficiency, thus leading eventually to organic disease

There are two known structures of protein (subunits) involved in thiamin uptake in prokaryocytes. Binding of thiamin to these proteins is strongly guided by electrostatic interactions. The lack of structural information about thiamin binding proteins for higher organisms remains a bottleneck for understanding the uptake process of thiamin in anatomic detail

The far-reaching complexity of thiamin uptake and its metabolism has been emphasized. As the primary gateway for the oxidation of glucose in energy synthesis, together with its binding of proteins, make it a candidate for explaining thiamin deficiency as the etiology of protein folding. Also, it has been shown that this deficiency is surprisingly common and may be responsible for altering the energy landscape. This hypothesis could easily be tested by including a valid laboratory test for thiamin deficiency in patients with proteopathies.