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.
Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders, which are characterized by selective neuronal destruction, synaptic malfunction and progressive cognitive and locomotor dysfunction. The major ones are Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis which are a formidable and growing global health and socio-economic burden mainly due to demographic aging. Even despite the advances in the symptomatic treatment, predominantly through the cholinergic, dopaminergic, glutamatergic, and GABAergic system, the current treatment regimens are not able to stop the underlying neurodegenerative events or reverse them. There is mounting evidence that convergent pathogenic mechanisms, such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, synaptic dysfunction, and chronic neuroinflammation, are convergent mechanisms. These convergent molecular and cellular cascades provide a strong rationale behind the identification of new neuropharmacological targets, which include: kinases, phosphatases, epigenetic regulators, neurotrophic signalling pathways and neuroimmune mediators. Advances in the biomarker discovery, genomics and systems biology have further enabled the use of precision based therapeutic stratification and early-intervention approaches. Genetic, nanotechnology, and RNA-based therapeutics as well as biologics are reconfiguring translational models in neurodegeneration. A mechanism-based, multi-target, precision neuropharmacological approach, as a group, has significant potential in achieving long-term neuroprotection, improved clinical and disease modification in neurodegenerative diseases.
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