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Axonal pathology in K rabbe's disease: The cytoskeleton as an emerging therapeutic target
Author(s) -
NogueiraRodrigues Joana,
Brites Pedro,
Sousa Mónica Mendes
Publication year - 2016
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23771
Subject(s) - neurodegeneration , microbiology and biotechnology , lipid raft , biology , axoplasmic transport , gsk 3 , microtubule , neuroscience , cytoskeleton , neuropathology , pi3k/akt/mtor pathway , protein kinase b , myelin , signal transduction , pathology , medicine , cell , central nervous system , biochemistry , disease
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.