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

Mol Neurobiol. 2022 Jan;59(1):683-702. doi: 10.1007/s12035-021-02557-w.

Tiziana Petrozziello ^# ¹, Evan A Bordt ^# ², Alexandra N Mills ¹, Spencer E Kim ¹, Ellen Sapp ³, Benjamin A Devlin ⁴, Abigail A Obeng-Marnu ², Sali M K Farhan ⁵ ⁶, Ana C Amaral ³, Simon Dujardin ³, Patrick M Dooley ³, Christopher Henstridge ⁷ ⁸, Derek H Oakley ³, Andreas Neueder ⁹, Bradley T Hyman ³, Tara L Spires-Jones ⁷, Staci D Bilbo ² ⁴, Khashayar Vakili ¹⁰, Merit E Cudkowicz ¹, James D Berry ¹, Marian DiFiglia ³, M Catarina Silva ³ ¹¹, Stephen J Haggarty ³ ¹¹ ¹², Ghazaleh Sadri-Vakili ¹³ ¹⁴

Affiliations

1 Sean M. Healey & AMG Center for ALS at Mass General, Massachusetts General Hospital, Boston, MA, 02129, USA.
2 Department of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
3 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
4 Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
5 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
6 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA, 02142, USA.
7 Centre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
8 Division of Systems Medicine, Neuroscience, Ninewells hospital & Medical School, University of Dundee, Dundee, UK.
9 Department of Neurology, Ulm University, 89081, Ulm, Germany.
10 Department of Surgery, Boston Children's Hospital, Boston, MA, 02125, USA.
11 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
12 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02114, USA.
13 Sean M. Healey & AMG Center for ALS at Mass General, Massachusetts General Hospital, Boston, MA, 02129, USA. gsadrivakili@mgh.harvard.edu.
14 MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Bldg 114 16th Street, R2200, Charlestown, MA, 02129, USA. gsadrivakili@mgh.harvard.edu.
# Contributed equally.

PMID: 34757590 DOI: 10.1007/s12035-021-02557-w

Abstract

Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer's disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach. Our findings demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro. Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS. As previously reported, electron microscopy revealed a significant decrease in mitochondria density and length in ALS mCTX. Lastly, reducing tau levels with QC-01-175, a selective tau degrader, 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 selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro.

Keywords

Amyotrophic lateral sclerosis; Hyperphosphorylated tau; Mitochondrial dynamics; Mitochondrial dysfunction; Tau degrader.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-134850

QC-01–175

99.94%, PROTAC Tau降解剂

PROTACs; Tau Protein

Neurological Disease

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