Regulation of cathepsin D activity by the FTLD protein progranulin

Excerpt

Progranulin (PGRN) protein, encoded by the granulin (GRN) gene, has been recently implicated in several neurodegenerative diseases [2, 5]. While haploinsufficiency of PGRN leads to frontotemporal lobar degeneration (FTLD) [2, 5], the most prevalent form of early onset dementia after Alzheimer’s disease (AD), complete loss of PGRN is known to cause neuronal ceroid lipofuscinosis (NCL) [1, 13], a group of lysosomal storage diseases. PGRN is a secreted glycoprotein of 7.5 granulin repeats [2, 5]. However, within the cell, PGRN is localized to lysosomes through two independent trafficking pathways [8, 17]. Furthermore, GRN is transcriptionally co-regulated with a number of essential lysosomal genes by the transcriptional factor TFEB [3]. While all these studies suggest an essential role of PGRN in regulating lysosomal function, how PGRN does so is still unclear. …