Loss-of-function mutations in progranulin， a lysosomal glycoprotein， cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders， but there are critical unresolved mechanistic questions about a progranulin gene therapy approach， including its potential to reverse existing pathology. Here， we address these issues using an AAV vector (AAV-) to deliver progranulin in mice (both male and female)， which model aspects of NCL and FTD pathology， developing lysosomal dysfunction， lipofuscinosis， and mic... More
Loss-of-function mutations in progranulin， a lysosomal glycoprotein， cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency causes neuronal ceroid lipofuscinosis (NCL). Progranulin replacement is a rational therapeutic strategy for these disorders， but there are critical unresolved mechanistic questions about a progranulin gene therapy approach， including its potential to reverse existing pathology. Here， we address these issues using an AAV vector (AAV-) to deliver progranulin in mice (both male and female)， which model aspects of NCL and FTD pathology， developing lysosomal dysfunction， lipofuscinosis， and microgliosis. We first tested whether AAV- could improve preexisting pathology. Even with treatment after onset of pathology， AAV- reduced lipofuscinosis in several brain regions of mice. AAV- also reduced microgliosis in brain regions distant from the injection site. AAV-expressed progranulin was only detected in neurons， not in microglia， indicating that the microglial activation in progranulin deficiency can be improved by targeting neurons and thus may be driven at least in part by neuronal dysfunction. Even areas with sparse transduction and almost undetectable progranulin showed improvement， indicating that low-level replacement may be sufficiently effective. The beneficial effects of AAV- did not require progranulin binding to sortilin. Finally， we tested whether AAV- improved lysosomal function. AAV-derived progranulin was delivered to the lysosome， ameliorated the accumulation of LAMP-1 in mice， and corrected abnormal cathepsin D activity. These data shed light on progranulin biology and support progranulin-boosting therapies for NCL and FTD due to mutations. Heterozygous loss-of-function progranulin () mutations cause frontotemporal dementia (FTD) and homozygous mutations cause neuronal ceroid lipofuscinosis (NCL). Here， we address several mechanistic questions about the potential of progranulin gene therapy for these disorders. mutation carriers with NCL or FTD exhibit lipofuscinosis and mouse models develop a similar pathology. AAV-mediated progranulin delivery reduced lipofuscinosis in mice even after the onset of pathology. AAV delivered progranulin only to neurons， not microglia， but improved microgliosis in several brain regions， indicating cross talk between neuronal and microglial pathology. Its beneficial effects were sortilin independent. AAV-derived progranulin was delivered to lysosomes and corrected lysosomal abnormalities. These data provide support for the efficacy of progranulin-boosting therapies for FTD and NCL.
