Understanding the Role of Autophagy and Transcription Factor EB (TFEB) in Krabbe Disease Pathogenesis

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Project Summary Krabbe disease (KD) is an inherited autosomal recessive, debilitating, lysosomal storage disorder (LSD) caused by mutations in galactosylcerebrosidase (Galc) gene. Galc deficiency leads to demyelination, neurodegeneration, and death within a couple years. Although therapies that delay the disease exist, there is currently no available cure for KD. Schwann cells-specific deletion of Galc (Galc-SC-cKO) in mice leads to a Peripheral Nervous System (PNS) pathological phenotype of KD, which includes accumulation of undigested substrates accompanied by demyelination, neurodegeneration, and a neuropathy very similar to the one observed in KD patients. Using this validated Galc-SC-cKO model, this study will investigate the degradative mechanisms that clear cellular substrate in the PNS, and how they contribute to development and pathogenesis of KD. Preliminary results indicate that macroautophagy is increased at the beginning of the disease, but it halts and decreases during disease progression. In addition, autophagosome accumulation in Schwann cells is observed under electron microscopy (EM) during disease progression. In contrast, chaperone-mediated autophagy pathway does not appear to contribute significantly to KD pathogenesis. I also find that the lysosomal transcription factor, TFEB, is increased during disease progression, suggesting an alteration in crosstalk between the lysosome and the nucleus in Schwann cells from Galc-SC-cKO mice. Thus, here I propose to study and manipulate macroautophagy and TFEB in Galc-SC-cKO mice in vivo. Defective autophagic clearance, suggested by accumulation of autophagosomes, accompanied by an altered TFEB-regulated lysosomal physiology may be leading to substrate accumulation and to lysosomal dysfunction, contributing to cellular demise in KD. Understanding specific mechanistic changes in degradative pathways could help pinpoint the cause and timing of substrate accumulation in KD and other LSDs. Such studies may also be relevant to other more common diseases caused by failure in lysosomes, autophagy, and proteostasis.