Researchers connect ALS hallmark to gene | News Center

Scientists who study amyotrophic lateral sclerosis know there are certain telltale features of the disease, and they occasionally find suspicious genes that seem to be connected to the development of ALS – but the two rarely align.

Now, a study led by researchers at Stanford Medicine and the Mayo Clinic has confirmed a connection between ALS’s most prominent molecular characteristic, a type of protein aggregate in the brain, and a gene that’s long been thought to contribute to the disease.

“We know that in about 98% of ALS cases, this erroneous protein aggregation forms,” ​​said Aaron Gitler, PhD, a Stanford Medicine professor of genetics. “And past genetic studies show that there’s a gene, UNC13A, that’s obviously connected to ALS. It’s on everyone’s radar, but no one knows how it contributes to the disease. This finding connects the two – the most common pathology with one of the most common genetic risk factors. ”

ALS, also known as Lou Gehrig’s disease, is a neurodegenerative condition that degrades nerve cell function and robs an individual of voluntary muscle movements. Walking, getting dressed or feeding oneself become virtually impossible as the disease progresses.

The discovery by Gitler and his group fills a big gap in the understanding of how ALS develops and could pave the way for a new treatment for the disease, which has no cure or effective therapies.

A paper describing the study published Feb. 23 in Nature. Gitler is the senior author. Rosa Ma, a graduate student in Gitler’s lab; Mercedes Prudencio, PhD, an assistant professor of neuroscience at the Mayo Clinic; and Yuka Koike, PhD, a postdoctoral scholar at the Mayo Clinic, share lead authorship.

Bad clumps

Neurons that exhibit clear signs of ALS often show the aggregation of a protein, called TDP43, outside its proper cellular home. Normally, TDP43 lives in the nucleus of a cell, where genes that encode the instructions to make a cell’s proteins are located. But in ALS, as the result of a poorly understood molecular glitch, TDP43 clumps outside the nucleus.

TDP43 is a crucial part of the protein-making process. Genes provide a template for proteins, but that genetic information needs to be preened and prepped before it can become a protein. That’s where TDP43 comes in: It engages in a quality-control-type role known as splicing, which cuts out superfluous molecular junk that can muck up an otherwise pristine protein.

In ALS, when TDP43 is missing from the nucleus and ejected into the cytoplasm – a sort of gel that bathes the cell’s other machinery – splicing does not always happen correctly. Instead, the genetic filler that’s usually cut remains in some protein templates, creating something called cryptic exons, which, in the case of ALS, are as nefarious as they sound.

Where does UNC13A fit in? When TDP43 is missing from the nucleus of a cell, it can no longer cut out the unnecessary scraps of genetic information in preparation for protein production, leading to cryptic exons. The resulting protein can have diminished function, and this is what happens with UNC13A. (Think of TDP43 as a delete button that edits typos out of a sentence, with that sentence being a long sequence of molecular information coding for the UNC13A protein.) Just like typos make sentences hard to read, these cryptic exons interfere with the cell’s ability to read the genetic instructions to make the proper proteins.

It’s important to note that the mutation in UNC13A, in itself, is not a cause of ALS. If TDP43 is present, like it is in a healthy cell, the pernicious snippet can be excised right out of the protein, Gitler said. ALS results from both a mutation in UNC13A and a dysfunctional TDP43, among other causes. In that sense, UNC13A is a “risk factor,” meaning that the mutation in UNC13A can help predict a person’s risk for developing the disease.

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