Frontotemporal dementia (FTD) is an early onset dementia and is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD is highly heritable with mutations in progranulin accounting for 5-26% of cases in different populations. Progranulin is involved in endocytosis, secretion and lysosomal processes, but its function under physiological and pathological conditions remains to be defined. Many FTD-causing nonsense progranulin mutations contain a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a major disease mechanism. Currently, there is no effective FTD treatment or therapy.

Aminoglycosides are a class of antibiotics that possess a less known function to induce eukaryotic ribosomal readthrough of PTCs to produce a full-length protein. The aminoglycoside-induced readthrough strategy has been utilized to treat multiple human diseases caused by PTCs. In this study, we tested the only clinically approved readthrough small molecule PTC124 and eleven aminoglycosides in a cell culture system on four PTCs responsible for FTD or a related neurodegenerative disease amyotrophic lateral sclerosis. We found that the aminoglycosides G418 and gentamicin B1 rescued the expression of the progranulin R493X mutation. G418 was more effective than gentamicin B1 (~50% rescue vs < 10%), and the effect was dose and time-dependent. The proganulin readthrough protein displayed similar subcellular localization as the wild-type proganulin protein. These data provide an exciting proof-of-concept that aminoglycosides or other readthrough-promoting compounds are a therapeutic avenue for familial FTD caused by proganulin PTC mutations.

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Published in Human Molecular Genetics.

This work is written by US Government employees and is in the public domain in the US.

The document available for download is the authors' post-peer-review final draft of the article.

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This study was supported, in part, by National Institutes of Neurological Disorder and Stroke Grant R01NS077284 and Department of Veteran Affairs Merit Review Award I01 BX002149 (to H.Z.), National Institutes of Health Blueprint for Neuroscience R01 AA027074 and Department of Veterans Affairs Merit Review Award I01 BX002978 (to E.J.H.), the Japan Society for the Promotion of Science and Ochanomizu University Scholarship (to K.H.), and National Institutes of Neurological Disorder and Stroke Grant R01NS070899 (to M.S.G.).