Tau Protein in Alzheimer’s Linked to ALS Mitochondrial Dysfunction
An abnormal version of tau, a protein associated with Alzheimer’s disease, may contribute to the progression of amyotrophic lateral sclerosis (ALS) by damaging mitochondria in neurons, according to a new study.
The findings suggest that decreasing tau levels might be a new therapeutic strategy to lessen mitochondrial dysfunction in ALS.
“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,” Ghazaleh Sadri-Vakili, PhD, said in a press release. Sadri-Vakili is senior author of the study and director of the Healey Center for ALS at Massachusetts General Hospital.
The study, “Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis,” was published in the journal Molecular Neurobiology.
Mitochondria, the so-called powerhouses of the cell, are organelles responsible for generating energy, among many other crucial roles. Dysfunction of mitochondria in neurons (nerve cells) is characteristic of ALS; however, the mechanisms behind this dysfunction are poorly understood.
Tau is a protein that normally is important for maintaining cellular structure, and shuttling molecular cargo to different parts of the cell. However, when tau becomes hyperphosphorylated — a kind of chemical modification involving the addition of many phosphate groups — it forms abnormal clumps or tangles in cells.
Tangles of hyperphosphorylated tau are characteristic of Alzheimer’s disease, and evidence suggests that hyperphosphorylated tau contributes to mitochondrial dysfunction in Alzheimer’s. Emerging research suggests that this abnormal form of tau also can be found in brain cells from people with ALS.
Now, an international team led by researchers at Massachusetts General Hospital conducted a series of experiments to investigate whether hyperphosphorylated tau also might drive mitochondrial dysfunction in ALS.
The team first examined post-mortem brain tissue from ALS patients, and demonstrated that hyperphosphorylated tau was present in their neurons — specifically in synapses, which are the places where neurons connect to “talk” to each other. Similar results were found across different types of ALS.
In subsequent lab experiments done with cells in culture, the team demonstrated that exposure to hyperphosphorylated tau leads to abnormalities in neuronal mitochondria, resulting in “a significant decrease in mitochondrial length and volume,” the researchers wrote.
This was accompanied by signs of oxidative stress, a type of cell damage characteristic of mitochondrial dysfunction. The team also confirmed these findings in the post-mortem ALS brain samples, in which consistent “alterations in mitochondrial density, mass, or morphology” were found, they wrote.
Further experiments showed that hyperphosphorylated tau induced mitochondrial dysfunction through interactions with a mitochondrial protein called DRP1. This interaction is a known mechanism of how tau drives mitochondrial problems in Alzheimer’s.
The researchers showed that mitochondrial dysfunction could be lessened by reducing the levels of either DRP1 or tau.
“We demonstrated that reducing tau with the specific tau degrader, QC-01-175, mitigated alterations in mitochondrial morphology, similar to knocking down DRP1,” they wrote, noting that degrading tau in this manner also lessened oxidative stress.
Based on the results, the team suggested that decreasing tau may provide a new strategy to reduce mitochondrial dysfunction in ALS.
“Our data provide the groundwork to assess QC-01-175 as a novel potential therapeutic strategy to improve mitochondrial morphology and function, and, in turn, motor neuron survival in ALS,” they concluded.