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.

Hematopoietic Stem Cell Transplantation in Late‐Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post‐allograft

“…NAA has historically been used as a marker for axons, but very recent evidence suggests that since NAA is also documented in oligodendrocytes, it may more accurately reflect the coupling between axons and myelin . Other evidence for axonal pathology includes an increase in D para , implying faster water diffusion along the axon which could occur as a result of axonal swellings and/or the destabilization of axonal cytoskeleton, neurofilament, and microtubules that occurs in Krabbe disease . Reduced FA, although by no means specific to axons, is modulated by their presence, and thus could be interpreted as a reduction in axonal packing.…”

Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases

“…Substrate accumulation in KD leads to the formation of globoid cells, which are large multinucleated macrophages surrounding cerebral blood vessels in white matter, and leukodystrophy, a state of demyelination and gliosis (Miyatake and Suzuki, 1972 ). At the cellular level, the recruitment of signaling proteins to lipid rafts is impaired, endocytosis is disrupted and axonal transport is severely compromised during disease (Nogueira-Rodrigues et al, 2016 ). There are both infantile and late-onset forms of KD.…”

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

“… A summary of the impact of psychosine on different cellular targets and pathways. Additional references for this figure: Peripheral nervous system: Schwann Cells [Apoptosis, Membranous inclusions, and Mitochondrial abnormalities ( 61 )], NMJ [Atrophy ( 62 ), Decreased innervation of muscle ( 62 ), and Akt pathway inhibition ( 62 )], and Axon [Demyelination/Dysmyelination/Swelling ( 63 , 64 ), GSK3B activation ( 42 ), Increased cytoskeletal density ( 65 ), Microtubule and neurofilament instability ( 64 )]. Bone Marrow: Architecture [Large endothelial gaps ( 66 ), Inhibition of endothelial cell proliferation ( 66 )].…”