Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis
Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis
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 abstractbiorxiv;2021.03.22.436505v1/UFIG1F1ufig1pTau-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.
Berry James D.、Petrozziello Tiziana、Haggarty Stephen J.、Amaral Ana C.、Dujardin Simon、Henstridge Christopher、Oakley Derek H.、Cudkowicz Merit E.、DiFiglia Marian、Silva M. Catarina、Farhan Sali M.K.、Mills Alexandra N.、Devlin Benjamin A.、Sadri-Vakili Ghazaleh、Obeng-Marnu Abigail A.、Bilbo Staci D.、Vakili Khashayar、Spires-Jones Tara L.、Neueder Andreas、Hyman Bradley T.、Sapp Ellen、Kim Spencer E.、Dooley Patrick M.、Bordt Evan A.
Sean M. Healey & AMG Center for ALS at Mass General, Massachusetts General HospitalSean M. Healey & AMG Center for ALS at Mass General, Massachusetts General HospitalDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School||Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School||Department of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolCentre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, UK||Division of Systems Medicine, Neuroscience, Ninewells hospital & Medical School, University of DundeeDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolSean M. Healey & AMG Center for ALS at Mass General, Massachusetts General HospitalDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School||Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical SchoolAnalytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 7 Cambridge CenterSean M. Healey & AMG Center for ALS at Mass General, Massachusetts General HospitalDepartment of Psychology and Neuroscience, Duke UniversitySean M. Healey & AMG Center for ALS at Mass General, Massachusetts General HospitalDepartment of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School||Department of Psychology and Neuroscience, Duke UniversityDepartment of Surgery, Boston Children?ˉs HospitalCentre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, UKDepartment of Neurology, Ulm UniversityDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolSean M. Healey & AMG Center for ALS at Mass General, Massachusetts General HospitalDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School
神经病学、精神病学基础医学分子生物学
Berry James D.,Petrozziello Tiziana,Haggarty Stephen J.,Amaral Ana C.,Dujardin Simon,Henstridge Christopher,Oakley Derek H.,Cudkowicz Merit E.,DiFiglia Marian,Silva M. Catarina,Farhan Sali M.K.,Mills Alexandra N.,Devlin Benjamin A.,Sadri-Vakili Ghazaleh,Obeng-Marnu Abigail A.,Bilbo Staci D.,Vakili Khashayar,Spires-Jones Tara L.,Neueder Andreas,Hyman Bradley T.,Sapp Ellen,Kim Spencer E.,Dooley Patrick M.,Bordt Evan A..Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis[EB/OL].(2025-03-28)[2025-05-06].https://www.biorxiv.org/content/10.1101/2021.03.22.436505.点此复制
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