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

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.

AAV‐mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice

“…The anti‐aging and cognition‐enhancing gene KL can act through its pleiotropic protective functions to counteract the diverse signaling cascades and mechanisms underlying senescence (Moos et al, 2020). Therapeutic approaches increasing KL gene expression can prevent further neurodegeneration and memory loss associated with aging and Alzheimer's disease (AD) (Abraham et al, 2016; Dubal et al, 2015).…”

“…Therapeutic approaches increasing KL gene expression can prevent further neurodegeneration and memory loss associated with aging and Alzheimer's disease (AD) (Abraham et al, 2016; Dubal et al, 2015). Although KL is mainly expressed in the kidney and does not cross the blood‐brain barrier (BBB) (Leon et al, 2017), it is also expressed in the brain (Masso et al, 2015; Moos et al, 2020). Our study used intracerebroventricular administration of AAVs as a delivery approach to increase KL expression in the CNS as a promising therapeutic strategy to normalize some relevant aging hallmarks present in SAMP8 mice.…”

“…Among them, the chronokine Klotho (KL) is an exciting candidate due to its pleiotropic anti‐aging protection (Abraham et al, 2016; Dubal et al, 2015; Kuro‐o et al, 1997). KL is involved in pathways that drive age‐related chronic disorders such as kidney disease, tissue dysfunction, neurodegenerative diseases, and cancer, among others (Moos et al, 2020; Semba et al, 2014). The Klotho gene is predominantly expressed in the kidney and choroid plexus in the brain as two main transcripts (Shiraki‐Iida et al, 1998).…”

Klotho Proteini ve Tip 2 Diabetes Mellitus

“…The KL protein is almost 130 kDa with a putative signal sequence at the N-terminus, a single transmembrane domain near the C-terminus and a short cytoplasmic domain (Razzaque et al, 2012). KL is a single-pass trans-membrane protein secreted in the brain, kidney, eye, testis, ovary, pancreas, pituitary and parathyroid gland tissues (Kuro-o, 2010;Moos et al, 2020). The KL protein family has three members: alpha, beta and gamma.…”

Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure

“…Although recent reports doubt if this endogenous transcript produces a functional protein 4 , different groups have reported that increasing the levels of s-KL or KL1 through recombinant protein administration or gene transfer approaches confers clear beneficial properties [5][6][7][8] . Klotho can modulate several pathways related to aging progression, which include among others, the inhibition of insulin growth factor-1 (IGF-1)/insulin signaling and Wnt pathways, involved in senescence and fibrosis, respectively 9 . It also reduces oxidative stress and exhibits anti-inflammatory effects, reducing cellular damage during aging 10 .…”