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

> **NIH NIH F31** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $30,887

## Abstract

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.

## Key facts

- **NIH application ID:** 10312884
- **Project number:** 1F31NS124106-01
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Narayan Dhimal
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,887
- **Award type:** 1
- **Project period:** 2021-08-16 → 2023-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312884

## Citation

> US National Institutes of Health, RePORTER application 10312884, Understanding the Role of Autophagy and Transcription Factor EB (TFEB) in Krabbe Disease Pathogenesis (1F31NS124106-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312884. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*