From biology to therapy: advances in progranulin-related neurodegenerative diseases
TL;DR
A lysosome-centered framework for understanding PGRN-related neurodegenerative pathologies is presented, and TMEM106B is discussed as a critical genetic modifier within this lysosomal network, highlighting its role in shaping disease risk and phenotypic heterogeneity.
Abstract
Altered PGRN expression or function has been implicated in a broad spectrum of neurodegenerative disorders, including frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and neuronal ceroid lipofuscinosis, as well as in age-associated brain aging. Despite substantial advances, the mechanisms by which PGRN deficiency drives neurodegeneration remain incompletely understood. Growing evidence converges on lysosomal dysfunction as a central pathogenic mechanism, linking impaired protein and lipid degradation, dysregulated neuroinflammatory signaling, and increased neuronal vulnerability. In this review, we summarize recent molecular, cellular, and translational studies to present a lysosome-centered framework for understanding PGRN-related neurodegenerative pathologies. We further discuss TMEM106B as a critical genetic modifier within this lysosomal network, highlighting its role in shaping disease risk and phenotypic heterogeneity. Finally, we critically evaluate emerging therapeutic strategies aimed at restoring PGRN levels, outlining both their translational promise and current limitations.