Farnesyl Transferase Inhibition for the Treatment of Tauopathies

Abstract

Tau inclusions are a shared feature of many neurodegenerative conditions and tau mutations lead to frontotemporal dementia. Approaches to treatment of these conditions have focused directly on the tau protein by targeting its post-translational modifications, its levels and its tendency to aggregate. We discovered a novel regulatory pathway for tau degradation that operates through the Rhes protein, a GTPase. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced Rhes, attenuated behavioral abnormalities, significantly reduced atrophy, tau inclusions, sumoylation and ubiquitination, as well as microgliosis in the rTg4510 tauopathy mouse. Direct reduction of Rhes levels reproduced the results observed with lonafarnib. The mechanism of lonafarnib action, as mediated by Rhes to reduce tau pathology, operates through the lysosome without involvement of the proteasome. Finally we show that the developmental increase in Rhes levels can be homeostatically regulated in the presence of tau mutations as a protective mechanism through which cells sense abnormal tau before any pathology is present. The extensive human trials of lonafarnib for other conditions, makes this drug ideal for repurposing to treat tauopathies.\n\nOne-sentence summaryVia a mechanism that involves targeting Rhes, lonafarnib can induce lysosomal-mediated tau degradation and prevent pathology in a tau mouse model