In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers.
Importantly, this effect on GCase activity was rescued by treatment with saposin C. Together, these findings suggested that reduced GCase activity due to impaired processing of prosaposin may contribute to pathogenesis of FTD resulting from PGRN mutations.
We identified 9 potentially pathogenic mutations in the AD-causal genes APP, PSEN1, PSEN2, and 6 mutations in a group of non-AD dementia-causal genes including the FTD-causal gene GRN and the VaD-causal gene NOTCH3.
Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia.
Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more.
The generation of in vivo models of FTD involves either targeting genes with known disease-causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP-43 and FUS.
Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers).
AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models.
Here, we address these issues using an AAV vector (AAV-<i>Grn</i>) to deliver progranulin in <i>Grn</i><sup>-/-</sup> mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis.
In the case of frontotemporal dementia (FTD), the ability to measure PGRN/GP88/GEP levels in plasma and cerebrospinal fluid may be useful in distinguishing PGRN mutation carriers among FTD populations at large.