Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis

• DOI: 10.1007/s12035-021-02557-w
• Publication Date: 2021-11-10T06:02:36Z
• Authors: Tiziana Petrozziello; Evan A. Bordt; Alexandra N. Mills; Spencer E. Kim; Ellen Sapp; Benjamin A. Devlin; Abigail A. Obeng-...; Sali M. K. Farhan; Ana C. Amaral; Simon Dujardin; Patrick M. Dooley; Christopher Henst...; Derek H. Oakley; Andreas Neueder; Bradley T. Hyman; Tara L. Spires-Jones; Staci D. Bilbo; Khashayar Vakili; Merit E. Cudkowicz; James D. Berry; Marian DiFiglia; M. Catarina Silva; Stephen J. Haggarty; Ghazaleh Sadri-Va...
• Keywords: Male; name=Neurology; 610; /dk/atira/pure/subjectarea/asjc/2800/2804; tau Proteins; /dk/atira/pure/subjectarea/asjc/2800/2808; 03 medical and health sciences; Cell Line, Tumor; Humans; Hyperphosphorylated tau; Phosphorylation; Aged; Aged, 80 and over; Neurons; 0303 health sciences; Amyotrophic Lateral Sclerosis; Middle Aged; Amyotrophic lateral sclerosis; Mitochondria; Oxidative Stress; Synapses; Mitochondrial dynamics; Tau degrader; Female; Mitochondrial dysfunction; name=Cellular and Molecular Neuroscience

AbstractUnderstanding 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 connectivityin 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 stressin 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.Graphical abstractpTau-S396 mis-localizes to synapses in ALS.ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentationin vitro.pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS.Reducing tau with a specific degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stressin vitro.