Research ArticleNeurodegenerative Disease

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

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Science Translational Medicine  12 Apr 2017:
Vol. 9, Issue 385, eaah5642
DOI: 10.1126/scitranslmed.aah5642

Connecting the dots in neurodegenerative disease

Heterozygous GRN mutations lead to progranulin haploinsufficiency and cause frontotemporal dementia (FTD) in the elderly population, whereas homozygous GRN mutations cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease that mainly affects children. The underlying relationship between progranulin-deficient FTD and NCL remains unexplored. Now, Ward et al. show that patients with heterozygous GRN mutations exhibit clinical and pathological features that are strikingly similar to NCL. Like NCL patients, individuals with heterozygous GRN mutations accumulate storage material throughout the central nervous system, and their cells exhibit signs of lysosomal dysfunction. These findings implicate lysosomal dysfunction as a central mechanism in both GRN-associated FTD and NCL.