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NIH Record - 75th Anniversary - National Institutes of Health

Scientists Discover New Molecular Pathway Shared by Two Neurodegenerative Disorders

Scientists from two independent research teams have discovered how the mislocalization of a protein, known as TDP-43, alters the genetic instructions for UNC13A, providing a possible therapeutic target that could have implications in treating amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and other forms of dementia. The studies were published in Nature.

ALS and FTD are two neurodegenerative disorders in which many cases are linked by mislocalization of TDP-43.

One study, a collaboration between NINDS and the University College London, initially looked at lab-grown neurons derived from human-induced pluripotent stem cells (iPSCs)—stem cells created from a patient’s tissue sample, often skin or blood. Using powerful genetic tools, the researchers created neurons that made much less TDP-43 protein than normal, resulting in the appearance of abnormal mRNA sequences called cryptic exons.

The UNC13A gene is important for maintaining the connections between neurons and has been shown to be a risk factor for both ALS and FTD. UNC13A is also one of the mRNA sequences that contained cryptic exons when TDP-43 was reduced. Cryptic exons were also seen in neurons taken from postmortem tissue of ALS and FTD patients. These findings directly link a well-established risk factor for ALS and FTD with the loss of TDP-43.

“We have built on years of genetic research that identified that UNC13A was implicated in motor neuron disease and FTD and supported it with a new molecular biology finding that confirms the gene is absolutely fundamental to the disease process,” said NINDS scientist Dr. Michael Ward.

At the same time, researchers from Stanford and the Mayo Clinic in Florida were analyzing postmortem neurons from patients with FTD or ALS. When genes were compared between neurons with and without TDP-43, UNC13A again emerged as one that was significantly affected by TDP-43 loss. 

Both studies provide clues toward strategies to prevent the death of neurons in these disorders.

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