Research ArticleNeurodegenerative Disease

A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy

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Science Translational Medicine  27 Mar 2019:
Vol. 11, Issue 485, eaat3005
DOI: 10.1126/scitranslmed.aat3005

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A rheostat for tau pathology

Tau inclusions are a prominent feature of many neurodegenerative diseases and are considered to be a potential therapeutic target. Hernandez et al. now report a previously unrecognized pathway leading to tau clearance via the lysosome. Activation of this pathway by inhibiting the enzyme farnesyltransferase blocks the attachment of a neuronal protein, Rhes, to the cell membrane. Farnesyltransferase inhibitors are already in use in human patients for treating cancer. The authors treated a mouse model of tauopathy with one such drug, lonafarnib, and were able to prevent the formation of tau inclusions, decrease microgliosis and brain atrophy, and attenuate behavioral abnormalities.