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Identification of TRPML1 agonists for the treatment of lysosomal-storage disorders

Friday, September 18, 2015 — Poster Session V

2:00 p.m. – 3:30 p.m.
FAES Terrace


  • NJ Martinez
  • RR Calvo
  • NT Southall
  • H Xu
  • X Zhang
  • Q Gao
  • L Yu
  • J Marugan
  • M Ferrer


Mutations of Mucolipin Transient Receptor Potential 1 (TRPML1) are the root cause of type IV mucolipidosis (ML4), a devastating neurodegenerative disease in young children characterized by mental retardation, motor defects and retinal degeneration. Currently there is no treatment for ML4. TRPML1 is localized to the membranes of late endosomes and lysosomes and mediates Ca2+ and Fe2+ efflux from these compartments into the cytosol. Under physiological conditions, TRPML1 regulates membrane trafficking by transducing information about levels of PI(3,5)P2, a low-abundance endolysosome-specific phosphoinositide, into changes in juxtaorganellar Ca2+, thereby triggering membrane fusion events in the late endocytic pathways. In addition, TRPML1 mediates release of Fe2+ from late endosomes and lysosomes, which is essential for cellular iron metabolism. In ML4 cells, the problems are twofold. First, defective Ca2+-dependent membrane trafficking causes accumulation of lipids and other bio-materials in the lysosome. Second, the lysosomal Fe2+ overload, converts the accumulated materials into non-degradable “lipofuscin”, which dramatically compromises lysosomal function. We hypothesized that stimulating TRPML1’s channel activity in the lysosome using synthetic agonists can restore lysosomal homeostasis in ML4 and other lysosomal-storage disorders such as Nieman Pick type C (NPC). We performed a high throughput screen (HTS) using cell-based Ca2+-imaging assays against a collection of >400,000 compounds. We identified and validated novel activators of TRPML1. Our current efforts are focused on the optimization and characterization of lead molecules through several functional assays including their ability to rescue lysosomal trafficking and storage defects in cells lines derived from patients with ML4 and NPC diseases.

Category: Neuroscience