# Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $107,666

## Abstract

SUMMARY
Lysosomal function is crucial for cell homeostasis, autophagy, nutrient sensing, apoptosis and tissue
remodeling. In lysosomal storage disorders (LSDs), characterized by genetic defects leading to anomalous
accumulation of metabolites in lysosomes, cells are affected by lysosomal malfunction frequently leading to cell
death. Cystinosis is a lysosomal storage disorder resulting from defects in the cystine transporter cystinosin
(CTNS). Increased levels of intra-lysosomal cystine lead to cell malfunction and progressive tissue
deterioration, which is especially manifested in kidneys. As with most LSDs, this leads to a slow but irreversible
deterioration, organ dysfunction and early death. Patients with nephropathic cystinosis develop proximal tubule
cell dedifferentiation, Fanconi syndrome and progressive renal injury, which are not corrected by the current
therapy, cysteamine. Thus, cell malfunction and tissue failure occur despite cystine depletion, suggesting that
cystine accumulation is not the only cause of all the defects observed in cystinosis. We recently revealed a
defective mechanism of chaperone-mediated autophagy (CMA) in cystinosis. Defective CMA is directly linked
to human disease, including kidney pathologies and neurological disorders. CMA defects in cystinosis are
caused by mislocalization and downregulation of the only lysosomal CMA receptor, LAMP2A. Defective CMA
activity correlates with high susceptibility to cell death in cystinosis. Importantly, the defect was not rescued by
cystine depleting therapies supporting that it is independent of lysosomal overload. Our data highlight that CMA
impairment is an important contributor to the pathogenesis of cystinosis and underline the need for new
treatments to complement cystine depletion therapies. Our research plan aims to elucidate the molecular and
cellular mechanisms leading to abnormal CMA activity in cystinosis. We also propose translational approaches
that utilize small-molecule activators of CMA to improve cellular function in cystinosis. Our Specific Aims are:
Aim 1: To understand the molecular basis of the regulation of LAMP2A function in cystinosis. To this end, we
will study the interplay between the CTNS protein and the CMA receptor LAMP2A and elucidate the
mechanisms that mediate LAMP2A trafficking and destabilization at the lysosomal membrane in cystinosis. Aim
2: To determine the molecular basis of the regulation of CMA activity and proximal tubule cell function in
cystinosis. We will study the mechanisms mediated by CTNS to regulate CMA function and will test the
hypothesis that the rescue of LAMP2A expression and CMA activity improves the function of proximal tubule
cells from cystinotic patients. Aim 3: To utilize small-molecule CMA activators in vivo to improve renal function
in cystinotic mice. We will correct cellular and renal function in cystinotic mice using CMA activators, alone, or
in combination with cysteamine. Our research is highly significant be...

## Key facts

- **NIH application ID:** 10801704
- **Project number:** 3R01DK110162-06S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Sergio Daniel Catz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $107,666
- **Award type:** 3
- **Project period:** 2017-08-09 → 2025-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801704

## Citation

> US National Institutes of Health, RePORTER application 10801704, Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis (3R01DK110162-06S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10801704. Licensed CC0.

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