Genomes and Genes
Combined neuroprotection and metabolic correction to treat leukodystrophies
Principal Investigator: ERNESTO ROQUE BONGARZONE
Abstract: DESCRIPTION (provided by applicant): Galactosylceramidase (GALC) deficiency in Krabbe disease (KD) causes toxic accumulation of galactosylsphingosine (psychosine) in myelin-forming cells, leading to demyelination of the nervous system. To reduce demyelination, current therapies seek to provide the missing enzyme to myelinating glia via infiltrating macrophages after the transplantation of bone marrow cells (BMT) from healthy donors into affected patients. Although the experience gained from this approach supports the use of BMT, KD patients suffer neurological sequelae. This suggests that the pathogenic mechanisms in KD are more complex than previously thought and that new therapeutic strategies are needed to cure KD. Experiments in our laboratory using the Twitcher mouse, a natural model for KD, indicate: 1) BMT- treated mice show neuronal and axonal damage by the time sufficient therapeutic enzyme accumulates in the nervous system ;2) psychosine is also produced and accumulates in neurons in the absence of mutant glia, causing the blockage of fast axonal transport via the activity of protein phosphatase 1 (PP1);and 3) mutant neurons show abnormal intracellular levels of Ca linked to deregulated expression of the Na+ Ca exchanger (NCX1). These observations suggest that GALC-deficient neurons mount a stress response that contributes to the pathology and that PP1 and NCX1 are two potential key components in the mechanism that mediates axonal defects in KD. Thus, we hypothesize that the deficiency of GALC in KD not only affects myelination but also triggers intrinsic and contemporaneous defects in neurons. To test this hypothesis we propose specific experiments to modulate PP1 and NCX1 activities in Twitcher neurons. These experiments will provide proof-of-concept that neuroprotective strategies can synergize with/improve the therapeutic benefits of traditional BMT-based treatments. Specifically, we will: 1) determine whether controlled and specific reduction of neuronal PP1 activity using siRNA specific silencing protects axonal transport in mutant neurons;2) determine whether flecainide, an antiarrhythmic drug with a proven ability to reduce sodium channel firing and NCX1 activity, improves NCX1-mediated influx of calcium in axons;and 3) determine whether these neuroprotective strategies combined with metabolic correction after BMT in newborn Twitcher mice improve clinical outcome. Results from these experiments will shed light on the molecular role of PP1 and NCX1 activity mediating neuronal dysfunction in KD and will provide a unique opportunity to improve the current BMT-based metabolic corrective strategies used to treat this leukodystrophy. The insight obtained will be relevant to other lysosomal storage disorders, which like KD are associated with aggressive neurological deterioration and for which there are no available cures. PUBLIC HEALTH RELEVANCE: Krabbe disease is a lysosomal storage disease that results in demyelination of the brain and nerves in affected individuals. Some Krabbe patients are treated with hematogenous cell replacement, which delays the onset of symptoms. However, a definitive and complete cure for this disease has not been achieved and treated patients continue to undergo deterioration and neurological deficits. The role of neuronal loss in Krabbe disease is not completely understood, but a consensus is emerging that dysfunction of axons and neurons leads to permanent neurological deficits in several neurodegenerative disorders, including multiple sclerosis, Alzheimer disease, Parkinson disease and others. Our preliminary studies provide evidence that Krabbe disease is compounded by axonal defects. In addition to the loss of myelin, neurodegeneration is likely a limiting factor in reducing the efficiency of traditional therapies. Thus, a combined therapy that provides not only enzyme replacement but also neuroprotection is likely to synergize or enhance the therapeutic benefits. Our objective is to examine whether two novel neuroprotective strategies targeting specific aspects of neurodegeneration in Krabbe disease can be combined with traditional bone marrow transplantation to fully prevent development of the disease. Results of the proposed experiments will provide proof-of-concept for the design of combined neuroprotective therapies to treat human Krabbe patients and the rational basis for studies of other leukodystrophies that involve degeneration of axons and myelin.
Funding Period: 2009-09-01 - 2014-08-31
more information: NIH RePORT
- Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe diseaseA B White
Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois, USA
J Neurosci Res 89:352-64. 2011..This work describes a mechanism that may contribute to limiting the in vivo efficacy of traditional therapies for KD...
- Axonopathy is a compounding factor in the pathogenesis of Krabbe diseaseLudovico Cantuti Castelvetri
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, MC512, Chicago, IL 60612, USA
Acta Neuropathol 122:35-48. 2011..Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants...
- Psychosine induces the dephosphorylation of neurofilaments by deregulation of PP1 and PP2A phosphatasesLudovico Cantuti-Castelvetri
Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA
Neurobiol Dis 46:325-35. 2012..We propose that a psychosine-driven pathogenic mechanism through deregulated phosphotransferase activities may be involved in this process...
- MMP-3 mediates psychosine-induced globoid cell formation: implications for leukodystrophy pathologyKumiko Ijichi
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06510, USA
Glia 61:765-77. 2013..Hence, elevated expression of MMP-3 in GLD may promote microglial responses to psychosine that may represent an important pathophysiological process in this disease and its treatment...
- Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe diseaseGregory B Potter
Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
Hum Mol Genet 22:3397-414. 2013..Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis...
- The sphingolipid psychosine inhibits fast axonal transport in Krabbe disease by activation of GSK3β and deregulation of molecular motorsLudovico Cantuti Castelvetri
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, USA
J Neurosci 33:10048-56. 2013..This study identifies psychosine as a pathogenic sphingolipid able to block fast axonal transport and is the first to provide a molecular mechanism underlying dying-back degeneration in this genetic leukodystrophy...
- Neuronal inclusions of α-synuclein contribute to the pathogenesis of Krabbe diseaseBenjamin R Smith
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, University of Illinois Chicago, Chicago, IL, 60612, USA
J Pathol 232:509-21. 2014..This study demonstrates the occurrence of neuronal deposits of fibrillized proteins including α-synuclein, identifying Krabbe disease as a new α-synucleinopathy...
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