Abstract
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.
pTau-S396 mis-localizes to synapses in ALS.
ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in 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 stress in vitro.
Competing Interest Statement
B.T.H. is a member of Novartis, Dewpoint, and Cell Signaling Scientific Advisory Board (SAB), and of Biogen DMC, and acts as consultant for US DoJ, Takeda, Virgil, W20, and Seer; he receives grants from Abbvie, F prime, NIH, Tau consortium, Cure Alzheimer fund, Brightfocus, and JPB foundations. T.S.J. is on the scientific advisory board of Cognition Therapeutics and receives grant funding from European Research Council (grant 681181), UK Dementia Research Institute, MND Scotland, and Autifony. M.E.C. acts as consultant for Aclipse, Mt Pharma, Immunity Pharma Ltd., Orion, Anelixis, Cytokinetics, Biohaven, Wave, Takeda, Avexis, Revelasio, Pontifax, Biogen, Denali, Helixsmith, Sunovian, Disarm, ALS Pharma, RRD, Transposon, and Quralis, and as DSBM Chair for Lilly. J.D.B. has received personal fees from Biogen, Clene Nanomedicine and MT Pharma Holdings of America, and grant support from Alexion, Biogen, MT Pharma of America, Anelixis Therapeutics, Brainstorm Cell Therapeutics, Genentech, nQ Medical, NINDS, Muscular Dystrophy Association, ALS One, Amylyx Therapeutics, ALS Association, and ALS Finding a Cure. S.J.H. is or/has been a member of the SAB and equity holder in Rodin Therapeutics, Psy Therapeutics, Frequency Therapeutics, and Souvien Therapeutics, and has received consulting or speaking fees from Sunovion, Biogen, AstraZeneca, Amgen, Merck, Juvenescence, Regenacy Pharmaceuticals, and Syros Pharmaceuticals, and funding from F-Prime, Tau Consortium, Alzheimer Association/Rainwater Foundation Tau Pipeline Enabling Program and the Stuart & Suzanne Steele MGH Research Scholars Program. None of these had any influence over the current paper.