Axonal Neuropathy and Protein Aggregation: Novel Mechanisms of Neurodegeneration in Krabbe Disease.

In this study two novel mechanisms of neurodegeneration were identified in a murine model of Krabbe Disease (KD). KD is an autosomal recessive disease, where mutations in the gene for lysosomal enzyme β-Galactosylceramidase (GALC) are responsible for toxic accumulations of the sphingolipid galactosylsphingosine (psychosine). The work presented here will outline previously undescribed mechanisms of axonal loss and cell body dysfunction that likely contribute to the neurologic pathology of KD. Previous studies showed the twitcher (TWI) mouse, a bona-fide model for KD undergoes structural abnormalities in axons of the spinal cord and sciatic nerve and these abnormalities present before the onset of demyelination. Using this information it was hypothesized that neurons undergo a dying back neuropathy of axonal processes that lead to neurologic dysfunction. To challenge this hypothesis we analyzed the activation of caspase-3 in axons of the TWI mouse. This study will present the first evidence of caspase activation in axons of the TWI mouse and show that psychosine is sufficient to induce this activity. This evidence builds on the hypothesis that individuals with KD undergo a dying back neuropathy in the central and peripheral nervous system. How dying back neuropathies translate to neuronal cell body damage or death is still unclear. Many mechanisms of neuronal cell death have been implicated from axonal transport defects to abnormal processing and aggregation of proteins. Interestingly, aggregation of α-synuclein, which is known to play a pathogenic role in various neurological conditions such as Parkinson disease (PD), has been recently found also in some human lysosomal storage diseases. Thus, we hypothesized that α-synuclein inclusions are present in KD and are likely induced by psychosine. This study will show that α-synuclein does significantly aggregate in specific regions of the TWI brain and that psychosine increases the rate of aggregation in vitro. This is the first of abnormal neuronal α-synuclein inclusions in a model of KD and supports the hypothesis that psychosine accumulation may act as a seed for aggregation. In summary, these studies have identified two novel mechanisms of neurodegeneration in the mouse model of KD. These findings will aid the study of KD by offering new therapeutic approaches for KD patients, as well as, new areas of study for neurodegenerative protein aggregating diseases.