Elucidating a mechanistic link between progranulin & lysosomal function in Alzheimer Disease

This study explores the role of progranulin (PGRN) in regulating lysosomal pH and its downstream effects on inflammation in neurodegenerative diseases. Progranulin is a multifunctional signaling protein whose biological activity depends on how it is proteolytically processed into smaller subunits. Growing evidence links PGRN deficiency to both lysosomal dysfunction and chronic neuroinflammation—two hallmarks of disorders such as Alzheimer’s disease and frontotemporal dementia.

The authors investigate how PGRN processing influences lysosomal function and proinflammatory signaling using two distinct human cell models. The SW13 adrenal carcinoma cell line, which exists in epigenetically distinct subtypes, was used to examine differences in lysosomal pH and PGRN processing. The HMC3 human microglial cell line was used to assess microglial activation and cytokine production, providing insight into neuroinflammatory responses. Findings suggest that variations in PGRN expression and proteolytic processing are associated with changes in lysosomal acidity, cell growth rates, and inflammatory cytokine production.

Importantly, the study shows that appropriate processing of PGRN supports lysosomal protease activity and helps maintain normal lysosomal pH. In models of PGRN insufficiency, restoring PGRN levels improves lysosomal function and reduces inflammatory signaling. The results also indicate that changes in lysosomal pH may, in turn, influence how PGRN is processed, creating a feedback loop that modulates inflammation.

Overall, this work highlights a mechanistic link between PGRN processing, lysosomal acidification and microglial-driven inflammation. Because mutations in the PGRN gene are associated with disrupted lysosomal pH and multiple neurodegenerative diseases, targeting lysosomal regulation of PGRN may offer a promising therapeutic strategy to slow or prevent disease progression.