TY - JOUR
T1 - Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease
AU - Teixeira, Carla Andreia
AU - Miranda, Catarina Oliveira
AU - Sousa, Vera Filipe
AU - Santos, Telma Emanuela
AU - Malheiro, Ana Rita
AU - Solomon, Melani
AU - Maegawa, Gustavo H.
AU - Brites, Pedro
AU - Sousa, Mónica Mendes
N1 - Funding Information:
This work was funded by the European Leukodystrophy Association to M.M.S. and P.B. (ELA 2010-042C5 ) and by FEDER funds through the Operational Competitiveness Programme — COMPETE and by National Funds through FCT — Fundação para a Ciência e a Tecnologia under projects PTDC/SAU-ORG/112406/2009 (to P.B.) and PTDC/SAU-GMG/111761/2009 (to M.M.S.). G.H.M. is currently supported by the National Institutes of Health (NIH) through NIMH 1R03MH098689 and NIH-NINDS 1R01NS079655 grants, by the National MPS Society and by clinical research and educational grants from Genzyme-Sanofi , Biomarin Pharmaceuticals , Protalix and Shire HGT . C.O.M. was funded by Fundação para a Ciência e Tecnologia ( SFRH/BD/29768/2006 ), C.A.T. was supported by Programa Ciência, funded by POPH-QREN and MCTES . P.B. is an Investigator FCT. The authors declare no competing financial interests. The authors would like to thank Catarina Silva (IBMC) for the help in quantifying the co-localization of TrkA in endosomes and axonal transport of synaptophysin.
PY - 2014/6
Y1 - 2014/6
N2 - In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder.
AB - In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder.
KW - Axonal transport
KW - Endocytosis
KW - Krabbe's disease
KW - Leukodystrophy
KW - Myelin
KW - Twitcher
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UR - http://www.scopus.com/inward/citedby.url?scp=84896968554&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2014.02.012
DO - 10.1016/j.nbd.2014.02.012
M3 - Article
C2 - 24607884
AN - SCOPUS:84896968554
SN - 0969-9961
VL - 66
SP - 92
EP - 103
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -