Differential regulation of progranulin derived granulin peptides

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are differentially regulated compared to granulins A and B. Furthermore, we demonstrated that granulin B, C and E are heavily glycosylated and the glycosylation pattern of granulin C varies in different physiological and pathological conditions. Deficiency of lysosomal proteases leads to alterations in the levels of a specific subset of granulins. These data support that the levels of individual granulin peptides are differentially regulated under physiological and pathological conditions and provide novel insights into how granulin peptides function in the lysosome.