Alpha-synuclein aggregates are present in Parkinson’s disease. mRNAs of alpha-synuclein have iron-responsive elements in 5′ untranslated regions. Iron-responsive elements in mRNAs of iron regulated proteins bind iron regulatory proteins (IRP1 and IRP2) affecting stabililites of transcripts of iron regulated proteins. Iron levels can affect alpha-synuclein levels, however, apparently there is an asymmetry as to how iron affects alpha-synuclein levels. Iron chelators decrease alpha-synuclein levels though added iron does not increase alpha-synuclein levels. With alpha-synuclein homeostasis dysregulated via a dysregulated iron metabolism, rather than via high levels of alpha-synuclein per se, alpha-synuclein aggregates could form.
Hypoxia-inducible factor 1alpha (HIF-1α) induces transcription of thiamine transporter 2 by binding to the promoter of thiamine transporter 2. HIF-1α and hypoxia-inducible factor 2alpha bind to the same hypoxia responsive elements is promoters of hypoxia regulated genes. Hypoxia-inducible factor-2alpha is also called endothelial PAS domain-containing protein 1 (EPAS1).
EPAS1 mRNA has an iron response element in the 5′ untranslated region. Wheniron regulatory proteins(IRPs) bind to an iron response elements in the 5′ untranslated region of mRNA transcripts mRNA transcripts are destabilized reducing translation of iron responsive genes.
EPAS1 could like HIF-1α bind to promoters of the gene for thiamine transporter 2. However increased activity of IRP1 could destabilize EPAS1 mRNA transcripts reducing transcription of thiamine transporter 2 in response to hypoxia.
Neuropathy could result from increased activity of IRP1. With increased activity of IRP1 there could be low levels of EPAS1. Overtime with hypoxia not inducing thiamine transporter 2 the gene for thiamine tranpor 2 could become hypermethylated. Taking only RDA amounts of thiamine is then no longer sufficuent.
For neuropathy a combination of iron from carbonyl iron, thiamine and biotin could be of assistance.Irondecreases IRP1 activity which would stabilize mRNA transcipts of EPAS1 so thiamine transporter 2 can be induced by EPAS1. Thiamine and biotin supplementation can treat mutations in thiamine transporter 2.
When biotin is supplemented biotin is supplemented three times a day while pantothenic acid is supplemented once a day also but away from biotin. Intestinal absorption of biotin is via the sodium-dependent multivitamin transporter (SMVT) where the SMVT also transports pantothenate. High dosages of pantothenic acid taken at the same time as biotin could inhibit transport of biotin. Biotinylation of the SMVT locus inhibits transcription of the SMVT gene so biotin cannot be taken at the same time as pantothenic acid.
The SMVTalso transports lipoic acid. Supplementing with lipoic acid must be avoided as lipoic acid supplementation would competitively inhibit the transport of biotin and pantothenic acid by the SMVT.
There is no genetic defect nor is there a systematic thiamine deficiency where there is neuropathy arises due to high levels of IRP1. Only some thiamine transporter 2 genes are hypermethylated. Localized thiamine deficiencies do not have the symptoms of generalized thiamine deficiences, however, one of the symptoms of localized thiamine deficiencies could be neuropathy.
Synthesis of thiamine diphosphate by thiamine pyrophosphokinase requires ATP. Creatine buffers ATP. Creatine taken four times a day can be of asssistance in the treatment of neuropathy due to high levels of IRP1 as long as creatine is taken with iron from carbonyl iron, thiamine and biotin.
Vitamin B6 will worsen a neuropathy due to increased levels of IRP1 likely due to an effect on glutamic–pyruvic transaminase and serine-pyruvate transaminase which can not be supported due to dysregulation of aconitase 1 in the TCA cycle. Supplemental vitamin B6 could be of assistance given iron from carbonyl iron is supplemented.
Supplemental carbonyl iron, thiamine, biotin and pantothenic acid could be a more effective treatment for a lot of cases of neuropathy where supplemental vitamin B6 could also be assistance. Supplements and drinks on the list of ‘too be avoided supplements and drinks’ on the Treatment Page would have to be avoided.
Amyloid precursor protein (APP) mRNA has an iron response element (IRE) in the 5′ untranslated region. Iron regulatory 1 (IRP1) and and iron regulatory protein 2 (IRP2) when bound to the IRE in the 5′ untranslated regiondestablize transcripts of iron regulated proteins. IRP1 and IPR2 when bound to the IRE in amyloid precursor protein mRNA decrease translation of APP. Iron decreases levels of IRP1 and IRP2. A point of iron chelators in Alzhemeir’s disease is by decreasing iron levels to increase levels of IRP1 and IRP2 thereby decreasing transcripition of APP.
APP is the precusor of amybloid beta protein. Amyloid betacan form plaques which are associated with Alzheimer’s disease. Iron chelators by decreasing APP levels would decrease levels of amyloid beta protein which was thought for decades to be a very good thing. Very effective treatments for Alzheimer’s appeared imminent.
A very serious difficulty arose. Drugs that reduce levels of amyloid beta do not treat or slow the progression of Alzheimer’s disease.
APP can looked at from a different angle. Amyloid precursor protein when ablatedincreases iron retention in cells by decreasing iron export. Loss of tight control of APP translation not high levels of APP could be what is causing iron retention in neurons.
What I have been arguing is that IRP1 is dysregulated in a range of neurological illnesses, such as Alzheimer’s and that this can lead to iron accumulation in neurons and cell death. Tight control of iron levels, not reducing iron levels via iron chelation, could be part of a treatment for various neurological illnessse such as Alzheimer’s disease.
A meta-analysis indicate that serum iron is significantly lower in Alzheimer’s patients than in controls. Supplmental iron carbonyl given three time a day could be part of a treatment for Alzheimer’s disease. The goal, of course, would not be high iron levels but rather tightly regulated levels of IRP1 and IRP2. Iron homeostasis could be upset in Alzheimer’s disease which is a much different way of loooking at iron than ‘iron is toxic’ in Alzheimer’s disease.
Alpha synuclein mRNAhas an iron responive element in the 5′ untranlated region. Iron responive elementsin the 5′ untranlated region of mRNA when bound by iron responsive protein 1 (IRP1) or iron responive protein 2 (IRP2) destabilize transcripts of iron-regulated proteins. Increasing iron levels would decrease levels of IRP1 and IRP2 and increase levels of alpha synuclein which is held to be very bad.
Alpha synuclein can act as a ferrireductase reducing iron 3+ to iron 2+. Overexpressing human α-synuclein in nigral dopaminergic neurons demonstrated a correlation between α-synuclein expression and ferrireductase activity, however, in Parkinson’s patientsthere is a reduction of ferrireductase activity in brains.
What if the key fact about alpha synuclein in Parkinson’s patients is alpha synuclein aggregates form only after decreases in ferrireductase activity in Parkinson’s patients. High, constant but normal iron levels where iron levels are tightly regulated throughout the day could keep ferrireductase activity constant throughout the day preventing alpha synuclein aggregates from forming.
Supplemental iron from iron carbonyl could keep iron levels constant keeping ferrireductase activity of alpha synuclein constant preventing alpha synuclein aggregates from forming. There is no significant differencesin serum iron levels between controls and Parkinson’s patients. There are serious difficulties with iron in PD patients but these difficulties could stem from a loss of iron homeostasis which could be re-regulated by iron from iron carbonyl given three times a day.
This idea would, of course, have to be tested in rats before being tested in humans
The Major Histocompatibility Complex (MHC) has been associated with schizophrenia. The hemochromatosis gene, HFE, which regulates iron levels is linked to the MHC on chromosome 6. In cells that express HFE IRP1 and IRP2 bindingincreases as the labile iron pool decreases with increased HFE expression. IRP1 and IRP2 are regulated by iron levels. Genetic studies that have associated the MHC region with schizophrenia frequently conclude that this is evidence for an infectious etiology to schizophrenia as the MHC is involved in immunity. What genetic associations of the MHC to schizophrenia could be picking up is associations of HFE with schizophrenia where such associations arise due to dysregulations in iron metabolism.
Aconitase 1 (ACO1) is an enzyme in the citric acid cycle. Aconitase 1 is a dual function protein. Upon loss of an iron-sulfur cluster ACO1 becomes iron regulatory protein 1 (IRP1). IRP1 affects stability of mRNA transcripts of proteins involved in iron metabolism such as ferritin, DMT1, which is an iron transporter, and ferroportin, which is the only known iron exporter. Increasing iron levels switches IRP1 to ACO1 as IRP1 gains an iron-sulfur cluster. With a 4Fe-4S iron-sulfur cluster ACO1 can participate in the citric acid cycle and generate ATP.
On-off disorders could be are due to wide swings in ACO1/IRP1 and the TCA cycle. Suddenly the TCA cycle is functioning and then the TCA cycle is not functioning while at the same time there are swings in the regulation of iron regulated proteins. Dietary iron could be associated with swings in on-off symptoms.An added wrinkle is that high IRP1 levels adversely affects copper absorption, however, copper is needed for iron metabolism.
I very much like answers that answer everything. On-off symptoms are prominent in lots and lots of illnesses. There is, of course, bipolar disorder but a lot of depressions cycle rapidly and are some of the most difficult depressions to treat. Parkinson’s disease has a very prominent on-off symptoms. In Parkinson’s disease there are indications that iron metabolism is dysregulated. There could be a unitary explanation for cycling disorders.