The relevance of α-KLOTHO to the central nervous system: Some key questions.
α-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for FGF23, and as a soluble factor in serum. α-Klotho is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, α-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of α-Klotho, which we define as brain α-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain α-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain α-Klotho and other pools of α-Klotho, and for a greater understanding of the basic function of soluble α-Klotho. The mechanism by which the human KL-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of α-Klotho for the aging brain to become clear.
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
Marina Minto
MM
Cararo-Lopes
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
Caio Henrique Yokoyama
CHY
Mazucanti
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
Cristoforo
C
Scavone
Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
Elisa Mitiko
EM
Kawamoto
School of Life, Health & Chemical Sciences, The Open University, Milton Keynes MK7 6AA, United Kingdom. Electronic address: daniel.berwick@open.ac.uk.
Daniel Charles
DC
Berwick
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D005966:Glucuronidase / Q000096:biosynthesis*; D006801:Humans; D000090265:Klotho Proteins
C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
Aging; CNS; Cognition; KLOTHO; Signaling