title: Axonal pathology in Krabbe's disease: The cytoskeleton as an emerging therapeutic target.
abstract: In Krabbe's disease (KD), demyelination and myelin-independent axonal and neuronal defects contribute to the severe neuropathology. The toxic substrate that accumulates in this disease, psychosine, induces alterations in membrane lipid rafts with downstream consequences to cellular signaling pathways that include impaired protein kinase C, ERK, and AKT-glycogen synthase kinase-3β (GSK3β) activation. In addition to impaired recruitment of signaling proteins to lipid rafts, endocytosis and axonal transport are affected in KD. Defects in AKT-GSK3β activation, a central pathway regulating microtubule stability, together with alterations in neurofilaments and microtubules and severely defective axonal transport, highlight the importance of the neuronal cytoskeleton in KD. This Review critically discusses these primary neuronal defects as well as new windows for action opened by their identification that may contribute to effectively correct the neuropathology that underlies this disorder. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Nogueira-Rodrigues
authors.affiliation: Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Brites
authors.affiliation: Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. msousa@ibmc.up.pt.
authors.forename: Mónica Mendes
authors.initials: MM
authors.lastname: Sousa
mesh_terms: D001369:Axons / Q000378:metabolism / Q000473:pathology*; D003599:Cytoskeleton / Q000502:physiology*; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology* / Q000628:therapy*; D009474:Neurons / Q000473:pathology*; D011609:Psychosine / Q000633:toxicity
chemical_list: D011609:Psychosine
keywords: Krabbe's disease; axonal transport; leukodystrophy; lipid rafts; microtubule stability; twitcher mice