Neurodegenerative Diseases

Mutations in the progranulin gene have been linked to two distinct neurodegenerative diseases—frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), both associated with progressive cognitive decline. Growing evidence suggests that the protein progranulin plays a critical role in the lysosome, but how progranulin regulates lysosomal function and protects against neurodegeneration remains unknown.

Fenghua Hu, Molecular Biology and Genetics, and her team are conducting studies that will shed light on how progranulin regulates lysosomal function and provide new insights into the disease mechanism of FTLD. Results will facilitate therapeutic development for progranulin-related FTLD as well other neurodegenerative diseases with a reported role of progranulin, such as Alzheimer’s disease.  

The Hu lab has identified a protein called prosaposin as a binding partner with progranulin and have uncovered some of the mechanisms of how progranulin and prosaposin work together to regulate lysosomal function. They’ve found that progranulin-deficient mouse models and FTLD patients with progranulin mutations had reduced levels of prosaposin-derived peptides in the lysosome—linking prosaposin to the disease. They also showed that progranulin and prosaposin form a complex with particular proteases (cathepsin B and D) in the lysosome, which have also been associated with FTLD. The team is now working to validate the hypothesis that progranulin is critical for proper prosaposin and cathepsin functions, and that impaired prosaposin and cathepsin functioning is a key disease mechanism in FTLD.

NIH Award Number: 1R01NS095954-01A1

 

Cornell Researchers

Funding Received

$2 Million spanning 5 years