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Review
. 2020 Mar 31;9(1):94-105.
doi: 10.1089/biores.2020.0004. eCollection 2020.

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

Walter H Moos  1   2 , Douglas V Faller  3   4 , Ioannis P Glavas  5 , David N Harpp  6 , Iphigenia Kanara  7 , Anastasios N Mavrakis  8 , Julie Pernokas  9 , Mark Pernokas  9 , Carl A Pinkert  10 , Whitney R Powers  11   12 , Konstantina Sampani  13   14 , Kosta Steliou  4   15 , Demetrios G Vavvas  13   16 , Robert J Zamboni  6 , Krishna Kodukula  2 , Xiaohong Chen  13   16
Affiliations
Review

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

Walter H Moos et al. Biores Open Access. .

Abstract

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.

Keywords: Klotho; amyotrophic lateral sclerosis; mitochondria; multiple sclerosis; neurodegenerative disease.

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Conflict of interest statement

W.H.M., in addition to academic and nonprofit roles, is employed by ShangPharma Innovation, is a managing director of Pandect Bioventures, receives royalties from Elsevier as a book author, is a consultant for Aduro Biotech, receives royalty and equity sharing benefits from SRI International, has stock or other financial interests in Aduro Biotech, Azkarra Therapeutics, Rigel Pharmaceuticals and Valitor, and serves on the boards of directors and/or scientific advisory boards of Aprinoia Therapeutics, Circle Pharma, Global Blood Therapeutics, Rigel Pharmaceuticals, ShangPharma Innovation and Valitor. D.V.F., in addition to academic and nonprofit roles, is employed by Viracta Therapeutics, Phoenicia Biosciences, and Takeda Pharmaceuticals and serves as a consultant to Briacell Therapeutics. Kosta Steliou, in addition to academic and nonprofit roles, is the founder and chief scientific officer of PhenoMatriX. K.K. consults with and/or serves as an executive or on the boards of various biotechnology and pharmaceutical companies from time to time, where he may receive compensation and/or stock options, and he is eligible to receive compensation from ShangPharma Innovation and Pandect Bioventures, health care venture incubator and venture capital firms.

Figures

FIG. 1.
FIG. 1.
Sampling of neurologic conditions associated with mitochondrial dysfunction.
FIG. 2.
FIG. 2.
Monomethyl fumarate, the pharmacologically active form of Tecfidera and Vumerity.
FIG. 3.
FIG. 3.
Chemical structures of FDA-approved therapeutics for ALS, including cromolyn sodium, a drug used to treat asthma and other conditions showing promising potential as a repurposed drug for ALS. ALS, amyotrophic lateral sclerosis; FDA, Food and Drug Administration.
FIG. 4.
FIG. 4.
Klotho function in neurodegenerative disorders and/or dysregulated myelination.
See this image and copyright information in PMC

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