Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

Petrozziello, T.; Bordt, E. A.; Mills, A. N.; Kim, S. E.; Sapp, E.; Devlin, B. A.; Obeng-Marnu, A. A.; Farhan, S. M. K.; Amaral, A. C.; Dujardin, S.; Dooley, P. M.; Henstridge, C.; Oakley, D. H.; Neueder, A.; Hyman, B. T.; Spires-Jones, T. L.; Bilbo, S. D.; Vakili, K.; Cudkowicz, M. E.; Berry, J. D.; DiFiglia, M.; Silva, M. C.; Haggarty, S. J.; Sadri-Vakili, G.

doi:10.1101/2021.03.22.436505

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bioRxiv · 10.1101/2021.03.22.436505

Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

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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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/436505v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1d805baorg.highwire.dtl.DTLVardef@1601f49org.highwire.dtl.DTLVardef@1a62abforg.highwire.dtl.DTLVardef@40699f_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIpTau-S396 mis-localizes to synapses in ALS. C_LIO_LIALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. C_LIO_LIpTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. C_LIO_LIReducing tau with a specific degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro. C_LI

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Petrozziello, T., Bordt, E. A., Mills, A. N., Kim, S. E., Sapp, E., Devlin, B. A., Obeng-Marnu, A. A., Farhan, S. M. K., Amaral, A. C., Dujardin, S., Dooley, P. M., Henstridge, C., Oakley, D. H., Neueder, A., Hyman, B. T., Spires-Jones, T. L., Bilbo, S. D., Vakili, K., Cudkowicz, M. E., Berry, J. D., DiFiglia, M., Silva, M. C., Haggarty, S. J., Sadri-Vakili, G.. 2021-03-22. Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis. https://doi.org/10.1101/2021.03.22.436505

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