Summary: Post-mortem studies of brain tissue from ALS patients reveal an abnormal form of tau is present in novel brain areas, and the tau interacts with DRP1. The tau appears to cause the brain cell’s mitochondria to fragment and increase oxidative stress. Reducing tau reversed the effect, decreasing oxidative stress and mitochondrial fragmentation.
Source: Mass General
New research provides a better understanding of the mechanisms behind the development of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, and points to a potential treatment strategy.
The work was led by investigators at the Healey Center for ALS at Massachusetts General Hospital (MGH) and is published in Molecular Neurobiology.
ALS, a degenerative condition without a cure, attacks brain and spinal cord nerve cells to progressively affect individuals’ ability to move, speak, eat, and even breathe. Previous studies have implicated dysfunction within mitochondria, which generate energy within cells, as playing an important role in the development of ALS.
Also, studies in Alzheimer’s disease have linked changes in mitochondrial function to interactions between an abnormal form of tau, which accumulates in the brains of patients with Alzheimer’s disease, and a mitochondrial protein called dynamin-related protein 1 (DRP1).
Piecing these bits of information together, Ghazaleh Sadri-Vakili, PhD, director of the NeuroEpigenetics Laboratory at the MassGeneral Institute for Neurodegenerative Disease and the Healey Center for ALS at MGH, and her colleagues examined whether interactions between this abnormal tau with DRP1 might also promote mitochondrial dysfunction in ALS, and whether reducing tau could be a novel and promising therapeutic approach to fight the disease.
The team found that in brain tissue from deceased patients who had ALS, the abnormal form of tau is present, and was located where tau is not normally found. The tau interacts with DRP1.
When cells were grown in contact with deceased ALS patients’ brain tissue that contained abnormal tau, the cells’ mitochondria fragmented and oxidative stress increased. Importantly, reducing tau with a specific degrader reversed these effects, reducing mitochondrial fragmentation and lowering oxidative stress.
“We demonstrated for the first time that targeting tau with a new class of small molecules that selectively degrade it can reverse the ALS-induced changes in mitochondria’s shape and function, highlighting tau as a potential therapeutic target,” says Sadri-Vakili.
Co-authors include 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: Funding for the study was provided by 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.
Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis
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.