TMEM59 deficiency ameliorates disease-like pathologies in tauopathy model mice via activating chaperone-mediated autophagy

In the present study, we found that TMEM59 levels were increased in the brains of AD patients and the PS19 tauopathy mouse model at pathological stages. TMEM59 haploinsufficiency attenuated cognitive deficits, neurodegeneration, synapse dysfunction, gliosis, neuroinflammation, and tau pathology in PS19 mice. Moreover, we showed that TMEM59 interacted with HSC70 and LAMP2A, two CMA core components. TMEM59 deficiency increased LAMP2A protein levels and promoted CMA activity, whereas TMEM59 overexpression had the opposite effect. Together, our study identifies an important role of TMEM59 in regulating CMA activity and reveals the potential for targeting TMEM59 as novel tauopathy therapeutics.