Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

Abstract

SUMMARY The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell (iPSC) lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel GRN mutation (PGRN S116X). In neurons and microglia differentiated from PGRN S116X iPSCs, the levels of intracellular and secreted progranulin were reduced, establishing patient-specific cellular models of progranulin haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the PI3K and MAPK pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by progranulin expression. Our findings identify cell-autonomous, reversible defects in patient neurons with progranulin deficiency and provide a new model for studying progranulin-dependent pathogenic mechanisms and testing potential therapies.

Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders

“…Besides animal models, human induced pluripotent stem (iPS) cell lines have been generated from patients carrying a GRN or TARDBP mutation recapitulating different disease aspects (152, 153). Using this technology, neuronal cell models can be studied in the context of the same genetic background of the patient.…”

S6K2: The Neglected S6 Kinase Family Member

“…Mutations in progranulin (PGRN), a protein involved in cell growth and survival (83–85), are a common cause of FTD (86). Human neurons obtained from FTD patients with mutant PGRN were shown to have reduced cell viability that correlated with a downregulation of S6K2 transcription (87). All these changes were rescued by expression of wild-type PGRN, directly linking this factor with expression of S6K2.…”

The Emerging Roles of MicroRNAs in the Pathogenesis of Frontotemporal Dementia–Amyotrophic Lateral Sclerosis (FTD-ALS) Spectrum Disorders

“…Although the function of progranulin and its role in neurodegeneration remain largely unknown, many pathogenic mutations in progranulin are null mutations that lead to haploinsufficiency (Baker et al, 2006; Gass et al, 2006). Indeed, reduced progranulin expression in heterozygous GRN mice or in human neurons derived from patient-specific iPSCs results in disease-relevant behavioral or cellular phenotypes (Almeida et al, 2012; Filiano et al, 2013). …”