Tauopathy, including
Alzheimer Disease (AD), is characterized by
Tau protein accumulation and autophagy dysregulation. Emerging evidence connects
polyamine metabolism with the autophagy pathway, however the role of
polyamines in
Tauopathy remains unclear. In the present study we investigated the role of
spermine synthase (SMS) in autophagy regulation and
tau protein processing in Drosophila and human cellular models of
Tauopathy. Our previous study showed that Drosophila
spermine synthase (dSms) deficiency impairs lysosomal function and blocks autophagy flux. Interestingly, partial loss-of-function of SMS in heterozygous dSms flies extends lifespan and improves the climbing performance of flies with human Tau (hTau) overexpression. Mechanistic analysis showed that heterozygous loss-of-function mutation of dSms reduces hTau
protein accumulation through enhancing autophagic flux. Measurement of
polyamine levels detected a mild elevation of
spermidine in flies with heterozygous loss of dSms. SMS knock-down in human neuronal or glial cells also upregulates autophagic flux and reduces
Tau protein accumulation. Proteomics analysis of postmortem brain tissue from AD patients showed a significant albeit modest elevation of SMS
protein level in AD-relevant brain regions compared to that of control brains consistently across several datasets. Taken together, our study uncovers a correlation between SMS
protein level and AD pathogenesis and reveals that SMS reduction upregulates autophagy, promotes Tau clearance, and reduces
Tau protein accumulation. These findings provide a new potential therapeutic target of
Tauopathy.