Summary: Post-mortem analysis of brain tissue from people with amyotrophic lateral sclerosis (ALS) shows an abnormal, hyperphosphorylated form of tau protein mislocalized to novel brain regions where it is not normally found. This altered tau interacts with the mitochondrial fission protein DRP1, promoting mitochondrial fragmentation and increased oxidative stress. Applying a selective tau degrader reversed these changes in cell-based assays, reducing mitochondrial fragmentation and oxidative stress.
Source: Mass General
New research clarifies a possible mechanism driving degeneration in amyotrophic lateral sclerosis (ALS) and identifies tau protein as a promising therapeutic target.
Researchers at the Healey Center for ALS and the MassGeneral Institute for Neurodegenerative Disease at Massachusetts General Hospital (MGH) led the study, which appears in Molecular Neurobiology. The work focuses on links between abnormal tau protein, mitochondrial dysfunction, and oxidative stress in ALS.
ALS is a progressive, fatal neurodegenerative disease that destroys motor neurons in the brain and spinal cord, impairing movement, speech, swallowing, and breathing. Mitochondrial dysfunction—disruption of the cell’s energy-generating and metabolic machinery—has long been implicated in ALS pathology. In Alzheimer’s disease (AD), hyperphosphorylated tau is known to accumulate and interact with dynamin-related protein 1 (DRP1), a GTPase that mediates mitochondrial fission, leading to mitochondrial fragmentation and altered function.
To test whether a similar process occurs in ALS, Ghazaleh Sadri-Vakili, PhD, director of the NeuroEpigenetics Laboratory at Mass General, and colleagues examined post-mortem motor cortex tissue from patients with ALS. They focused on pTau-S396, a hyperphosphorylated tau species. Their analyses found that pTau-S396 is mislocalized to synapses in the motor cortex across ALS subtypes and that this abnormal tau co-occurs with increased levels of DRP1 in synaptic fractions.
In cell-based experiments, the team treated cultured cells with synaptoneurosomes—subcellular, synapse-enriched preparations—from brains of ALS patients that were enriched in pTau-S396. Cells exposed to these ALS synaptoneurosomes showed increased oxidative stress, marked mitochondrial fragmentation, and disrupted mitochondrial connectivity, even in the absence of immediate cell death. Electron microscopy of ALS motor cortex tissue corroborated these findings, revealing reduced mitochondrial density and shorter mitochondria in affected brain regions.
Crucially, the investigators tested whether lowering tau levels could prevent these mitochondrial changes. Using QC-01-175, a selective small-molecule tau degrader, they reduced tau in vitro and observed reversal of ALS synaptoneurosome–induced effects: mitochondrial fragmentation decreased and indicators of oxidative stress were lowered. These results demonstrate that targeting tau can counteract synapse-associated mitochondrial dysfunction linked to ALS pathology.
“We demonstrated for the first time that targeting tau with a new class of small molecules that selectively degrade it can reverse ALS-induced changes in mitochondrial shape and function, highlighting tau as a potential therapeutic target,” says Sadri-Vakili.
The multidisciplinary team of co-authors includes Tiziana Petrozziello, Evan A. Bordt, Alexandra N. Mills, Spencer E. Kim, Ellen Sapp, Benjamin A. Devlin, Abigail A. Obeng-Marnu, Sali M.K. Farhan, Ana C. Amaral, Simon Dujardin, Patrick M. Dooley, Christopher Henstridge, 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, and Stephen J. Haggarty.
Funding: The study received support from multiple sources including the Judith and Jean Pape Adams Charitable Foundation; the Byrne Family Endowed Fellowship in ALS Research; the ALS Canada Tim E. Noël Postdoctoral Fellowship; the Alzheimer’s Association; the Jack Satter Foundation; the Dr. and Mrs. E. P. Richardson, Jr Fund for Neuropathology at MGH; the Alzheimer’s Association/Rainwater Foundation Tau Pipeline Enabling Program; and the Stuart & Suzanne Steele MGH Research Scholars Program.
About this ALS research news
Author: Marcela Quintanilla Dieck
Source: Mass General
Contact: Marcela Quintanilla Dieck – Mass General
Image: The image is in the public domain
Original Research: Closed access. “Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis” by Ghazaleh Sadri-Vakili et al., Molecular Neurobiology.
Abstract
Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis
This study investigates how hyperphosphorylated tau contributes to mitochondrial dysfunction in ALS and evaluates whether reducing tau levels could be a therapeutic strategy. Prior work has established mitochondrial dysfunction as a central event in ALS pathogenesis, and Alzheimer’s disease research has shown that interactions between hyperphosphorylated tau and DRP1 can drive mitochondrial fission and dysfunction.
The authors report that pTau-S396 accumulates at synapses in the motor cortex across ALS subtypes and that ALS synaptoneurosomes enriched in this tau species elevate oxidative stress, induce mitochondrial fragmentation, and impair mitochondrial connectivity in vitro without causing immediate cell death. They further demonstrate that pTau-S396 physically interacts with DRP1 and that DRP1 is increased in synaptic fractions in ALS, supporting a mechanism of heightened mitochondrial fission. Electron microscopy confirmed reduced mitochondrial density and shorter mitochondria in ALS motor cortex tissue.
Finally, treatment with QC-01-175, a selective tau degrader, prevented mitochondrial fragmentation and reduced oxidative stress caused by ALS synaptoneurosomes in cell-based assays. Together, these findings support a model in which increased synaptic pTau-S396 drives mitochondrial fragmentation and oxidative stress via interaction with DRP1, and indicate that targeted reduction of tau may offer a novel approach to mitigate mitochondrial dysfunction in ALS.