Progranulin, lysosomal regulation and neurodegenerative disease

Abstract

The discovery that heterozygous and homozygous mutations in the gene encoding progranulin are causally linked to frontotemporal dementia and lysosomal storage disease, respectively, reveals previously unrecognized roles of the progranulin protein in regulating lysosome biogenesis and function. Given the importance of lysosomes in cellular homeostasis, it is not surprising that progranulin deficiency has pleiotropic effects on neural circuit development and maintenance, stress response, innate immunity and ageing. This Progress article reviews recent advances in progranulin biology emphasizing its roles in lysosomal function and brain innate immunity, and outlines future avenues of investigation that may lead to new therapeutic approaches for neurodegeneration.

Figure 1. Evolutionary dynamics of granulin domains and progranulin genes

A comparison of progranulin protein across selected species and model organisms is shown. Species cladogram based on established species phylogeny is shown on the left, and the corresponding progranulin proteins with complete granulin domains are shown on the right. Protein sequences corresponding to the longest progranulin isoform in each species as identified by Basic Local Alignment Search Tool (BLAST) were obtained from National Center for Biotechnology Information (NCBI) Protein database. Granulin domains were identified using the NCBI Conserved Domain Database and were plotted on the protein sequence using custom scripts.

Figure 2. Intracellular trafficking of progranulin and its role in lysosome biogenesis and function

Progranulin has been described as a secreted protein that undergoes endocytosis and intracellular trafficking to reach the lysosomes in microglia, neurons and tumour cells. a | In wild-type cells, progranulin is present in the Golgi apparatus and is secreted probably via the secretory pathway. Another structurally related protein, prosaposin, heterodimerizes with progranulin, and regulates the transport and secretion of progranulin. Once released in the extracellular space, progranulin undergoes sortilin-mediated endocytosis to reach the lysosome via a mechanism that is poorly understood. Another alternative and highly plausible mechanism for progranulin to reach the lysosome is through the recycling endosome, multivesicular body (MVB), late endosome and eventually to early lysosome. The transcription of GRN (which encodes progranulin) and of many lysosomal genes is under the control of the transcription factor TFEB. b | In the absence of progranulin, mouse Grn^−/−microglia show an expansion in the size of the late endosome and early lysosome but no defect in the expression of sortilin. Consistent with these findings, transcriptomic profiling in different regions of Grn^−/−mouse brain, including the cerebral cortex, hippocampus and cerebellum, shows age-dependent increases in the expression of genes related to lysosomal functions and to the innate immune system, including a marked increase the production of complement proteins, C1qa and C3 products, by microglia. For reasons that are not entirely clear, loss of progranulin increases the transcriptional activity of TFEB, which promotes a marked upregulation of lysosomal genes. As a consequence, Grn^−/−microglia and neurons exhibit features of lysosomal storage disease. Interestingly, over-expression of granulins can also lead to similar lysosomal defects. These results support the idea that a delicate balance of progranulin and granulin is crucial for the proper formation and function of lysosomes. ER, endoplasmic reticulum.

Figure 3. Progranulin deficiency disrupts glia–neuron homeostasis and promotes neurodegeneration during ageing

Emerging evidence indicates that, under physiological conditions, both microglia and astrocytes are required to maintain homeostasis in the brain. Results from transcriptomic and functional analyses of progranulin-deficient (Grn^−/−) mouse brains support the idea that progranulin functions as a ‘brake’ to suppress excessive microglial activation. In the ageing process, Grn^−/− microglia show age-dependent activation, characterized by enlarged cytoplasm and retracted processes, and a robust activation of the innate immunity system by increased production of complement proteins (such as C1qa and iC3b, the inactive product of cleaved C3b) and pro- inflammatory cytokines, which promotes synaptic pruning and causes cytotoxicity in neurons, respectively. Furthermore, microglial activation in Grn^−/−brains is accompanied by a marked increase in Grn^−/−astrocytes. These results suggest that loss of progranulin in microglia and astrocytes disrupts the homeostatic balance between these two cell types to promote neurodegeneration. Finally, loss of progranulin in neurons has also been shown to increase cellular stress and lysosomal defects that can further promote TAR DNA-binding protein 43 (TDP43) proteinopathy and cytotoxicity.