Differential regulation of progranulin derived granulin peptides

• Published in: Molecular neurodegeneration 2022-02, Vol.17 (1), p.15-15, Article 15
• Main Authors: Zhang, Tingting, Du, Huan, Santos, Mariela Nunez, Wu, Xiaochun, Pagan, Mitchell D, Trigiani, Lianne Jillian, Nishimura, Nozomi, Reinheckel, Thomas, Hu, Fenghua
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Brain; Cathepsin; Cathepsins; Comparative analysis; Demyelination; Enzymes; Estrogens; Females; Frontotemporal dementia; Frontotemporal lobar degeneration (FTLD); Frontotemporal Lobar Degeneration - metabolism; Gene expression; Glycosylation; Granulin; Granulins - metabolism; Haploinsufficiency; Intercellular Signaling Peptides and Proteins - metabolism; Liver; Lysosome; Lysosomes - metabolism; Male; Mice; Microglia; Mutation; Neurodegeneration; Neurons; Peptides; Physiological aspects; Progranulin (PGRN); Progranulins; Proteins; Signal transduction; Spleen; Viral antibodies
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-021-00513-9

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 regulated differently  compared to granulins A and B in various tissues. The levels of PGRN and granulin peptides vary in different brain regions and the ratio between granulins and PGRN is highest in the cortical region in the adult male mouse brain. Granulin-A is localized in the lysosome in both neurons and microglia and its levels in microglia increase under pathological conditions. Interestingly,  the levels of granulin A in microglia change correspondingly with PGRN in response to stroke but not demyelination. Furthermore, deficiency of lysosomal proteases and the PGRN binding partner prosaposin leads to alterations in the ratios between individual granulin peptides. Granulins B, C and E are heavily glycosylated and the glycosylation patterns can be regulated. Our results 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.