Infantile Krabbe disease (KD) (globoid cell leukodystrophy) is a devastating inborn degenerative disorder, which currently has no cure or effective long-term treatment. KD is primarily characterized by progressive demyelination, along with cognitive, muscular, and neurosensory deficits that ultimately result in death at a young age. KD pathology results from the toxic accumulation of unmetabolized galactosylsphingosine (psychosine) due to loss-of-function gene mutations for the lysosomal enzyme galactosylceramidase. While previous research has focused primarily on mitigating the effects of psychosine on myelin, demyelination does not provide an adequate explanation for some of the symptoms observed in KD, such as bradykinesia, muscle rigidity, and cognitive decline. With the idea that other pathogenic mechanism(s) contribute to KD, our laboratory has performed significant work to identify cellular and molecular aspects involved in neuronal and axonal dysfunction. Using the Twitcher (TWI) mouse, an enzymatically authentic model of KD, we found that axonopathy involves deficiencies in fast axonal transport and the axonal cytoskeleton, mediated by a psychosine-triggered alteration of phosphatase activities. Of importance, these pathogenic mechanisms appear to be independent of demyelination. Most recently, we have identified the presence of neuronal inclusions of aggregated alpha- synuclein (?-syn) in areas rich in psychosine in both human KD and TWI brain tissues. These findings may be relevant for understanding some aspects of KD neurodegeneration, considering that ?-syn is known to localize to the pre-synaptic terminal and has been implicated in the synthesis and release of dopamine (DA) at the synaptic junction. Synaptic function and the status of the dopaminergic system have never been studied in KD; however, these may bear a significant role in motor and cognition deficits in KD. In fact, preliminary studies for this application have identified: 1) decreased levels of DA, 2) reductions of DA's rate-limiting enzyme tyrosine hydroxylase (TH) in the TWI brain, and 3) reduced numbers of vesicles in the pre-synaptic terminal of TWI caudate neurons. We therefore hypothesize that a pathogenic mechanism initiated by deregulation of ?-syn represses TH activity and the synthesis of DA in nigrostriatal neurons, reduces these neurons' survival, and impairs DA synaptic transmission in KD. We plan to perform a set of experiments that utilize biochemical, ultrastructural, and electrophysiological techniques to answer this important question. This research will elucidate pathogenic aspects affecting motor and synaptic function in KD and will broaden the therapeutic targets available to patients suffering from this disease.

Public Health Relevance

Krabbe disease is a debilitating and ultimately fatal disorder, for which the treatment options are limited. Although typically characterized as a demyelinating disorder, the pathophysiology causing the cognitive and movement impairments seen in patients is not well understood. These symptoms could possibly be explained by the recent discovery of neuronal inclusions of aggregated alpha-synuclein, a protein that has been implicated in dopamine synthesis and the synaptic release of neurotransmitters in general. Investigating how these pathophysiological processes compound Krabbe disease is not only essential for developing novel therapeutics, but also has the potential to further our understanding of other alpha- synucleinopathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NST-2 Subcommittee (NST)
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Morris, Jill A
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University of Illinois at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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Abdelkarim, Hazem; Marshall, Michael S; Scesa, Giuseppe et al. (2018) ?-Synuclein interacts directly but reversibly with psychosine: implications for ?-synucleinopathies. Sci Rep 8:12462
Marshall, Michael S; Issa, Yazan; Jakubauskas, Benas et al. (2018) Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy. Mol Ther 26:874-889
Karumuthil-Melethil, Subha; Marshall, Michael S; Heindel, Clifford et al. (2016) Intrathecal administration of AAV/GALC vectors in 10-11-day-old twitcher mice improves survival and is enhanced by bone marrow transplant. J Neurosci Res 94:1138-51
Marshall, Michael S; Bongarzone, Ernesto R (2016) Beyond Krabbe's disease: The potential contribution of galactosylceramidase deficiency to neuronal vulnerability in late-onset synucleinopathies. J Neurosci Res 94:1328-32