New insights and therapeutic opportunities for progranulin-deficient frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common form of dementia. It affects the frontal and temporal lobes of the brain and has a highly heterogeneous clinical representation with patients presenting with a wide range of behavioral, language, and executive dysfunctions. Etiology of FTD is complex and consists of both familial and sporadic cases. Heterozygous mutations in the GRN gene, resulting in GRN haploinsufficiency, cause progranulin (PGRN)-deficient FTD characterized with cytoplasmic mislocalization of TAR DNA-binding protein 43 kDa (TDP-43) aggregates. GRN codes for PGRN, a secreted protein that is also localized in the endolysosomes and plays a critical role in regulating lysosomal homeostasis. How PGRN deficiency modulates immunity and causes TDP-43 pathology and FTD-related neurodegeneration remains an active area of intense investigation. In the current review, we discuss some of the significant progress made in the past two years that links PGRN deficiency with microglial-associated neuroinflammation, TDP-43 pathology, and lysosomal dysfunction. We also review the opportunities and challenges toward developing therapies and biomarkers to treat PGRN-deficient FTD.