Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics

Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer's disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN was a multifunctional protein involved in lysosomal function, neuroinflammation, and neuronal survival. This review discusses the contributions of GRN haploinsufficiency to FTD pathogenesis with an emphasis on genetic mutations, downstream cellular consequences, relevant animal and cellular models, and emerging therapeutic strategies. Loss-of-function mutations in GRN were responsible up to ~50% reduction in PGRN levels, resulting in lysosomal dysfunction, TDP-43 aggregation, impaired microglial homeostasis, and enhanced neuroinflammation. Multiple in vitro and in vivo models recapitulated these pathological features. Novel therapeutic approaches, such as AAV-mediated gene therapy, stop codon readthrough compounds, SORT1 inhibitors, and antisense oligonucleotides, were investigated to restore PGRN levels and to mitigate disease progressions. However, challenges included the oncogenic risks of overexpression and the limited translational success in clinical trials to date. Targeting GRN haploinsufficiency became a promising avenue for FTD therapy. Improved models and refined delivery systems would be essential to develop safe and effective treatments. Future work should also focus on biomarker-guided interventions in presymptomatic mutation carriers.