Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis
Evan A. Bordt,
Alexandra N. Mills,
Spencer E. Kim,
Benjamin A. Devlin,
Abigail A. Obeng-Marnu,
Sali M.K. Farhan,
Ana C. Amaral,
Patrick M. Dooley,
Derek H. Oakley,
Bradley T Hyman,
Staci D. Bilbo,
Merit E Cudkowicz,
James D. Berry,
M. Catarina Silva,
Stephen J Haggarty,
Posted 22 Mar 2021
bioRxiv DOI: 10.1101/2021.03.22.436505
Posted 22 Mar 2021
Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity in vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.
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