Granulin proteins (GRNs) as potential therapeutics for multiple neurodegenerative disorders caused by lysosome dysfunction and inflammation.
- Novel pathway and target provides new route for treatment.
- Granulins shown to rescue lysosomal defects in cell culture models.
Granulins are small proteins that are derived by proteolysis from full-length progranulin (PGRN). PGRN is cleaved into several granulin proteins, which are implicated in development, inflammation, cell proliferation and protein homeostasis. Previously, most investigators believed that PGRN acts in the extracellular space by activating signaling receptors on the neuronal surface or modulating inflammation (i.e. suppress excessive activation of microglia). Therefore, many therapeutic strategies to replace PGRN have focused on increasing the extracellular levels of PGRN. Though the precise functions of PGRN and granulins remain unclear, they are known to be linked to neurodegenerative diseases.
The inventor recently discovered PGRN is intracellularly routed to the lysosome and processed into stable, functional granulins. Dr. Kukar’s data suggest that granulins play a critical role in the normal function and homeostasis of the lysosome and, when decreased or absent, cause disease. The researcher is developing novel compositions of granulin as a therapy for individuals that harbor genetic variants or mutations in the GRN gene that decrease levels of PGRN/granulins. These novel granulins also have therapeutic potential in other neurodegenerative diseases with low PGRN/granulin levels or are caused by lysosomal dysfunction. This small protein has therapeutic potential against neurodegenerative diseases, including frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease, through a novel target and pathway.
- Animal data is available – recombinant human PGRN is processed into mature granulins in mouse cells and brains. Novel recombinant granulins can directly rescue lysosome dysfunction.
- Further experiments are underway.
Publication: Holler, C. J. et al. (2017). eNeuro. 4(4).
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