Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases

Abstract

We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe−/−xTfr2mut mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family ‘neurodegeneration with brain iron accumulation’ (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders.

Niemann-Pick’s disease type B and brain iron accumulation

“…[13] Expanded data mining and ontological analyses establish even a broader inter-relationship between abnormalities in myelin-related, lipid rich structures and iron. [4,14] At first sight, these observations prompted us to postulate that iron deposition in the brain might have been secondary to sphingomyelin dysmetabolism in our case, even though such a consequence of NP-B has not previously been reported.…”

Utility of susceptibility-weighted imaging in Parkinson’s disease and atypical Parkinsonian disorders

“…Iron functioning in the brain mainly exists in the forms of hemoglobin, iron-containing enzyme and non-haemin iron [ 13 , 28 , 45 ]. The iron involved in normal aging and neurodegenerative parkinsonism belongs to the non-haemin which is a cofactor of several enzymes that are associated with myelin formation and neurotransmitter production [ 13 , 27 – 29 , 45 , 50 , 51 ]. The period of the fastest iron deposition coincides with when the myelin of the brain forms the fastest in the early stage of life [ 12 , 29 , 45 ].…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…[50][51][52] Beyond AD and PD, age-related declines in Klotho 8,13,17,24,53 are associated with a range of other deteriorating central nervous system (CNS) processes. 17,24 For example, mounting evidence implicates dysregulation of Klotho in shared mechanistic pathological relationships linking iron and myelin in various common and rare brain diseases, [54][55][56] including abnormalities in myelination and the maturation of oligodendrocytes that are central to the pathogenicity of diseases such as multiple sclerosis (MS) 26,56,57 and amyotrophic lateral sclerosis (ALS). 56,58 OS Demyelination and Mitochondrial Dysfunction Mitochondrial dysfunction is a well-documented enabling factor in the pathophysiology of neurological conditions and disorders ( Fig.…”

“…114,117,118,[123][124][125] Dysregulated myelination is a characteristic feature of numerous heritable neurological diseases, such as the PNS hereditary disorder, Charcot-Marie-Tooth disease, 126,127 X-linked adrenoleukodystrophy and metachromatic leukodystrophy, 128 hereditary diffuse leukoencephalopathy with spheroids, Nasu-Hakola disease, 114 and Huntington's disease, 129,130 among others. 55,131,132 A dysfunctional myelination apparatus is also evident in acquired demyelinating diseases such as diabetic peripheral neuropathy, drug-related peripheral neuropathies, leprosy, and peripheral neuropathies of inflammatory etiology. 132 Most interestingly, converging evidence drawn from ''Big Data'' analytics in parallel with epigenetic, neuroimaging, and experimental model investigations seems to connect an adult-onset form of attention-deficit/ hyperactivity disorder pathogenesis and persistence with dysregulated myelination.…”

“…3,18,27,102,183,184 A soluble form of Klotho (sKlotho), primarily secreted from the kidney, circulates in blood, urine, and cerebrospinal fluid, exerting different biological effects in multiple tissues as a humoral factor. 5,6,8,52,[185][186][187][188][189] In the eye, Klotho protects against OS 53,55,58,153,190,191 and is essential to the proper maintenance and function of the ocular system, 12,26,[192][193][194][195] being expressed throughout the retina, with the highest levels in retinal ganglion cells. 196 The retinal pigment epithelium (RPE) is a highly specialized CNS tissue whose function is critical in preserving retinal homeostasis 53,78 and an age-dependent decline of Klotho expression is said to contribute to RPE degeneration and retinal pathology.…”