Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency

ABSTRACT This study investigates the cellular pathology resulting from haploinsufficiency of progranulin (PGRN) in frontotemporal dementia (FTD) associated with granulin (GRN) mutations. Utilizing fibroblasts from FTD patients carrying a distinctive GRN mutation (c.709-1G>A), we observed lysosomal and lipofuscin accumulation, impaired lysosomal function, compromised autophagic flux, and mitochondrial abnormalities. Notably, recombinant human progranulin (rhPGRN) treatment restored lysosomal acidification, mitigated mitochondrial defects, and demonstrated beneficial effects. FTD-GRN fibroblasts exhibited abnormal lipid metabolism with increased lipid droplet formation, influenced by GRN haploinsufficiency and modulated by rhPGRN. Under nutrient-rich conditions, lipid droplet dynamics were shaped by autophagy and mitochondrial processes, potentially due to impaired fatty acid oxidation. These findings highlight a direct association between GRN deficiency and altered lysosomal-mitochondrial interactions, influencing lipid metabolism and contributing to FTD pathogenesis. The documented lysosomal dysfunction, impaired autophagy, mitochondrial anomalies, and altered lipid metabolism collectively suggest a complex interplay of cellular processes in the development of FTD-GRN.