Neurology & Neurosurgery

ALS Study Reveals FUS as Key Player, Promising Therapeutic Target

May 17, 2024 - Eden McCleskey

Houston Methodist researchers have identified a key player and mechanism involved in the development of amyotrophic lateral sclerosis (ALS), a promising discovery that could open the door for future therapeutic interventions.

The discovery involves the establishment of a crucial link between mitochondrial health and the RNA-binding protein fused in sarcoma (FUS) and a novel pathway by which FUS may disrupt normal brain cell functionality in the devastating motor neuron disease.

"The extraordinary vision, scope and impact of this research will no doubt take time to reverberate throughout the greater scientific community, but we are eagerly anticipating what new scientific insights, inquiries and innovations will follow in its wake to improve the lives of current and future generations affected by this disease," said Dr. Gavin Britz, chief of Neurosurgery at Houston Methodist Hospital.

The study, published in Nature Communications in March, expands existing understanding of the normal role of FUS in mitochondrial DNA repair and maintenance and highlights the potential for strategies aimed at correcting repair defects and restoring mitochondrial function.

Dr. Muralidhar Hegde, a professor of Neurosurgery at Houston Methodist and study co-author, emphasized the need for a breakthrough for the terminal disorder: "People who are diagnosed with ALS today have essentially the same prognosis as Lou Gehrig did when he was diagnosed in 1939 — no effective therapies, no cures, with a life expectancy of two to four years. The disease has stubbornly resisted progress for far too long."

Know your enemy

Recognizing the pivotal role of mitochondria in neuronal health, Dr. Hegde and study co-author Dr. Manohar Kodavati focused their efforts on understanding how dysfunction in these cellular organelles contributes to the onset and progression of ALS.

"We knew from prior studies that this FUS protein was pathologically linked to ALS, a closely related disorder called frontotemporal dementia (FTD) and other neurodegenerative diseases, but we didn't know why," said Dr. Kodavati, a post-doctoral research fellow in Dr. Hegde's lab.

Through meticulous experimentation conducted on patient cells, mice models and human tissue samples and in collaboration with specialized labs and experts around the world, the researchers characterized the complete pathway and identified potential trigger points likely setting the process in motion decades before symptoms begin to occur.

Utilizing patient-derived ALS cell lines, transgenic mouse models and human autopsy samples, the team discovered that mutations in the FUS protein, whether hereditary or environmental, disrupted its collaboration with the DNA repair enzyme, Ligase 3.

In mitochondria, Ligase 3 is responsible for repairing normal wear and tear damage caused by reactive oxygen species, while FUS stabilizes Ligase 3 and facilitates its recruitment to damaged sites for timely repair.

"We discovered that mutations in the FUS protein can lead to compromised FUS functionality, compromised Ligase 3 performance and eventually the accumulation of mitochondrial DNA damage and cellular dysfunction — the hallmark of ALS pathology," Dr. Hegde explained.

Pick your battles

Armed with a new understanding of mitochondrial biology and inspired to translate their findings into tangible solutions for those afflicted by the disease, the researchers devised a series of cutting-edge experiments designed to bolster their insights and explore new avenues of therapeutic innovation.

Harnessing the power of CRISPR-Cas9 technology to correct FUS mutations in patient cells, the scientists successfully restored the function of the FUS protein, reversed mitochondrial dysfunction and confirmed FUS as a prime target for therapies aimed at staving off or preventing onset of disease.

Additionally, the researchers successfully delivered a nuclear DNA repair enzyme, Ligase 1, directly to mitochondria in cultured patient cells to demonstrate its potential to fill in for Ligase 3 in a pinch.

"By rectifying FUS mutations in patient-derived induced pluripotent stem cells and introducing targeted expression of an alternative DNA repair enzyme, Ligase 1, we were able to restore mitochondrial DNA integrity and mitochondrial function, suggesting a potential therapeutic approach for treating FUS-associated neurodegeneration," Dr. Kodavati summarized.

The study is also co-authored by professors Dale J. Hamilton at the Houston Methodist Center for Bioenergetics, Ludo Van Den Bosch at the University of Belgium, Wenting Guo at NeuroStra Institute in France and Alan Tomkinson at the University of New Mexico.

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ALS Research Neurosurgery