Deficient progranulin levels cause dose-dependent neurological syndromes: haploinsufficiency leads to frontotemporal lobar degeneration (FTLD) and nullizygosity produces adult-onset neuronal ceroid lipofuscinosis. Mechanisms controlling progranulin levels are largely unknown. To better understand progranulin regulation, we performed a genome-wide RNAi screen using an ELISA-based platform to discover genes that regulate progranulin levels in neurons. We identified 830 genes that raise or lower progranulin levels by at least 1.5-fold in Neuro2a cells. When inhibited by siRNA or some by submicromolar concentrations of small-molecule inhibitors, 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; several of these also raised progranulin levels in FTLD model mouse neurons. "Hit" genes regulated progranulin by transcriptional or posttranscriptional mechanisms. Pathway analysis revealed enrichment of hit genes from the autophagy-lysosome pathway (ALP), suggesting a key role for this pathway in regulating progranulin levels. Progranulin itself regulates lysosome function. We found progranulin deficiency in neurons increased autophagy and caused abnormally enlarged lysosomes and boosting progranulin levels restored autophagy and lysosome size to control levels. Our data link the ALP to neuronal progranulin: progranulin levels are regulated by autophagy and, in turn, progranulin regulates the ALP. Restoring progranulin levels by targeting genetic modifiers reversed FTLD functional deficits, opening up potential opportunities for future therapeutics development.
Frontotemporal dementia is the second prevalent dementia after Alzheimer's disease.• GRN mutations leading to PGRN deficiency are linked to frontotemporal dementia.• PGRN deficiency causes lysosome defects, neurodegeneration, and neuroinflammation.• Efforts to raise PGRN levels are a therapeutic strategy for frontotemporal dementia.
Haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), a devastating neurodegenerative disease with no effective treatment. PGRN is required for efficient proteostasis, as loss of neuronal PGRN results in dysfunctional lysosomes and impaired clearance and cytoplasmic aggregation of TDP-43, a protein involved in neurodegeneration in FTD. These and other events lead to neurodegeneration and neuroinflammation. However, the detailed mechanisms leading to protein dyshomeostasis in PGRN-deficient cells remain unclear. We report here the development of human cell models of FTD with PGRN-deficiency to explore the molecular mechanisms underlying proteostasis breakdown and TDP-43 aggregation in FTD. Neurons differentiated from FTD patient induced pluripotent stem cells (iPSCs) have reduced PGRN levels, and the neurons recapitulate key disease features, including impaired lysosomal function, defective TDP-43 turnover and accumulation, neurodegeneration, and death. Proteomic analysis revealed altered levels of proteins linked to the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS) in FTD patient neurons, providing new mechanistic insights into the link between PGRN-deficiency and disease pathobiology.
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