Klotho protein in neurodegenerative disorders

Torbus-Paluszczak, Magdalena; Bartman, Wojciech; Adamczyk-Sowa, Monika

doi:10.1007/s10072-018-3496-x

Cited by 42 publications

(31 citation statements)

References 48 publications

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“…In this context, the membrane-bound and the cleaved ectodomains of the klotho protein were observed to be associated with FGFR3 signaling. This protein acts as a co-receptor and was found to modulate the Wnt and IGF pathways, thereby enhancing remyelination in demyelinating animal models [139,140].…”

Section: Regulators Of Glia Cell Fate: Avenues To Adjust Aberrant Whimentioning

confidence: 99%

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Reiche

Küry

Göttle

2019

Cells

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Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.

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Section: Regulators Of Glia Cell Fate: Avenues To Adjust Aberrant Whimentioning

confidence: 99%

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Reiche

Küry

Göttle

2019

Cells

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“…7 Thus, nothing could be more appropriate than Klotho serving as a longevity gene. Indeed, once Klotho fails to adequately express its proteins and variants, 6,[8][9][10] it is implicated in pathways that drive agerelated chronic disorders such as kidney disease, tissue dysfunction, diabetic retinopathies, neurodegeneration, and impairments in mitochondrial function and muscle regeneration. 4,8,[11][12][13][14][15][16] a-Klotho is often referred to as an ''anti-aging protein.''…”

Section: Introductionmentioning

confidence: 99%

“…5,6,137,141,[144][145][146][147][148] In particular, FGF23 is a bone-derived hormone that in conjunction with Klotho acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. 5,6,14,23,102,136,138,145,148,149 Vitamin D regulates epigenetic mechanisms that maintain the transcription of its target genes in regulatory networks, including the expression of Klotho and nuclear factor-erythroid-2related factor 2 (Nrf2) to carry out many of its homoeostatic functions. 17,97,[150][151][152][153] Vitamin D is a modulator of the immune system, 154,155 hence its mention here, and accumulating evidence suggests vitamin D deficiency is a risk factor for dysregulated Klotho-associated neurodegenerative diseases, the most noteworthy being MS. 9,27,52,97,102,150,152,153,[156][157][158] Multiple Sclerosis MS is an insidious progressive neurodegenerative disease characterized by demyelinated lesions throughout the brain, spinal cord, and optic nerve resulting from immune-mediated attacks against myelin. [159][160][161]…”

Section: Introductionmentioning

confidence: 99%

“…The standard of chronic care, after using steroids for acute episodes, centers on the use of disease modifying therapies (DMTs) that modulate an overactive immune response, such as antibodies against interferon, interleukin, or related T cell targets. 9,[169][170][171][172] Unfortunately, although there is a growing armamentarium of DMTs for neurodegenerative diseases, they have to date had only a modest impact on disease progression 173,174 and thus the demand for myelin repair-promoting therapies for MS remains a significant unmet medical need. 159,[175][176][177][178] The discovery of new drugs is a daunting, lengthy, and costly endeavor.…”

Section: Introductionmentioning

confidence: 99%

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

Moos

Faller

Glavas

et al. 2020

BioResearch Open Access

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In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

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“…Klotho, a single-pass transmembrane protein, also known as an anti-aging protein, consists of 1012 amino acids [9][10][11]. The dysregulation of Klotho has been identified in several diseases and cancers such as chronic kidney disease, left ventricular hypertrophy, and thyroid cancer [10,12,13].…”

Section: Introductionmentioning

confidence: 99%

Klotho inhibits H 2 O 2 -induced oxidative stress and apoptosis in periodontal ligament stem cells by regulating UCP2 expression

Zhu

Xie

Liu

et al. 2020

Preprint

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Background Periodontitis, known as a human chronic inflammatory disease, has affected the life of millions of individuals. Known risk factors such as metabolic disease and oxidative stress have been reported to be closely associated with the initiation or development of periodontitis. However, the etiology of periodontitis remains unclear. Klotho, a single-pass transmembrane protein, has been widely reported to modulate cellular processes in various diseases. However, the role of Klotho in periodontitis is unknown.Results In this study, we designed and conducted a series of experiments to evaluate the role of Klotho in chronic periodontitis. Our experimental results showed that Klotho was downregulated in the gingival tissues, gingival crevicular fluid (GCF), and periodontal ligament stem cells (PDLSCs) of chronic periodontitis patients. Besides, Klotho upregulated the production of uncoupling protein 2 (UCP2) in H2O2-treated PDLSCs. In function, Klotho inhibited H2O2-induced oxidative stress and cellular apoptosis in PDLSCs. Moreover, the rescue assay suggested that UCP2 knock-down suppressed the effects of Klotho on H2O2-induced oxidative stress and apoptosis in PDLSCs.Conclusions In conclusion, we found that Klotho inhibits H2O2-induced oxidative stress and apoptosis in PDLSCs by regulating UCP2 expression. This novel discovery may provide a potential target for chronic periodontitis treatment.

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Klotho protein in neurodegenerative disorders

Cited by 42 publications

References 48 publications

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

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

Klotho inhibits H 2 O 2 -induced oxidative stress and apoptosis in periodontal ligament stem cells by regulating UCP2 expression

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