Figure 2. Cell biology of Progranulin (PGRN) deficiency in microglia.

(a) Secretion of PGRN can be mediated via the secretory and exophagy pathways. Once secreted, PGRN is endocytosed by binding with sortilin and M6PR and eventually reaches the lysosomes where it interacts with PSAP and regulates lysosomal acidification and degradation of cargoes. PGRN can interact with CpG and TLR9 to promote TNFα expression in innate immune response. In addition, PGRN can use sortilin-independent mechanism to transport from Golgi to late endosomes where it regulates vesicle trafficking from late endosomes to early lysosomes. In PGRN deficient microglia, there are increases in lysosomal storage materials, complement C3 and its cleavage product C3b, TMEM106B, PSAP and lipids. The excessive production of complement proteins, cytokines, and lipids in Grn^−/− microglia (b) Transcriptomic analyses in Grn^−/− thalamus show age-dependent microglial activation, characterized by overproduction of proinflammatory cytokines and complement proteins, C1q and C3b, from 7 to 12 months old. During this period, Grn^−/− microglia promote synaptic pruning and cause hyperexcitability in the thalamocortical circuit. From 12 to 24 months old, Grn^−/− microglia exhibit ameboid morphology and continue to produce excessive C1q, C3b, bioreactive lipids, and other unknown factors to accelerate neuronal cell death by compromising nuclear pore integrity and TDP-43 proteinopathy.