#MDA2021 – Rare WWOX Mutations in Patients Affect Mitochondria of Cells

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Variants in the WWOX gene may contribute to the development of amyotrophic lateral sclerosis (ALS) by affecting mitochondria, so that cells have lesser energy production and higher levels of toxic oxidative molecules, new research suggests.

Spencer Kim, at the Sean M. Healey & AMG Center for ALS at Mass General, presented the findings in a poster, “ALS-Linked Mutations in WWOX Lead to Mitochondrial Dysfunction” at the 2021 MDA Virtual Clinical and Scientific Conference.

The development of new therapies for ALS relies on the identification of targets that participate in key disease mechanisms.

The WWOX protein, coded by the gene of the same name, plays important roles in DNA repair, neurodegeneration, and oxidative stress — an imbalance in the production and clearance of toxic oxidative molecules. But it’s not known if alterations in the WWOX signaling pathway contribute to ALS.

To find out, Kim and colleagues investigated tissue samples collected from ALS patients and people without this disease (controls) to identify potential alterations in WWOX levels, and genetic variants in the WWOX gene.

Using post-mortem samples from the motor cortex, a part of the brain that controls the voluntary movement that is progressively lost in ALS, they found WWOX protein levels to be significantly lower in ALS patients compared with controls.

An analysis of data from Project MinE — which contains genomic information of 15,000 ALS patients and 7,500 controls to identify the genetic basis of the disease — also identified seven rare WWOX gene variants in ALS patients that were completely absent in controls.

Four of these variants were considered potentially pathogenic, or disease causing, based on their high Combined Annotation Dependent Depletion score (CADD), a tool for determining the damage that variants might do. One such mutation, dubbed WWOXSTOP261E, was located in a region of the gene important for the protein’s binding to mitochondria, the so-called energy producing factories of cells.

Given the potential role of WWOX in mitochondria function, the researchers examined the levels of mitochondrial proteins directly involved in energy production. Overall, ALS cortex samples had significantly lower levels of two of these proteins — ATP5A and COX II — than did control samples.

The WWOX protein was also found to directly interact with ATP5A, suggesting it may regulate how well mitochondria work within cells.

In a final experiment, investigators assessed how WWOX mutations affected cell survival and energy production. Culturing a nerve cell line with two mutated proteins significantly lessened survival compared with the normal, functioning WWOX protein.

While the protein deriving from the WWOXSTOP261E genetic variant did not change the length of mitochondria, it did lower energy production and raise levels of reactive oxygen species in cells.

Overall, these results suggest that “alterations in WWOX signaling may lead to mitochondrial dysfunction in ALS,” the researchers concluded.