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How proteins connect common neurodegenerative diseases

Cryptic exons (white) can be seen in cell nuclei (blue) in which there is little TDP-43 (green).Brown et al., Nature.

Neurodegenerative diseases lead to the progressive failure or death of nerve cells in the brain. Different brain changes underlie different types of neurodegenerative diseases. In frontotemporal dementia (FTD), nerve cells called neurons in the frontal and temporal lobes of the brain are damaged. This leads to dementia, which can cause forgetfulness, confusion, and trouble with memory. In amyotrophic lateral sclerosis (ALS), the nerve cells responsible for controlling voluntary muscle movements are affected.

A protein called TDP-43 has been tied to both ALS and FTD, along with other neurodegenerative diseases. TDP-43 is normally found in the cell’s nucleus. There, it helps in RNA splicing, the process in which mRNA transcripts—the instructions used to make proteins—are created. But in certain neurodegenerative diseases, TDP-43 forms abnormal clumps outside of the nucleus. Without TDP-43, abnormal genetic material, called cryptic exons, can be included in the mRNA transcript. This may result in a defective protein or prevent the protein from being made.

ALS and FTD also share a genetic risk factor: mutations in a gene called UNC13A. The protein made from this gene is important for maintaining the connections between nerve cells and for normal nerve cell functioning.

Two teams recently investigated how TDP-43 and the UNC13A gene mutations together contribute to disease. Their studies were funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results from both were published online on February 23, 2022, in Nature.

One team, led by Dr. Michael E. Ward at NINDS and Dr. Pietro Fratta at the University College London, created lab-grown neurons derived from human stem cells. The team genetically altered the neurons to make much less TDP-43 protein than normal. This resulted in cryptic exons appearing in UNC13A mRNA transcripts and less of the transcripts overall. The researchers determined that this was because the incorrectly spliced transcripts were marked for degradation.

The team also observed cryptic exons in the UNC13A transcripts of neurons collected from postmortem tissue of ALS and FTD patients. They found that neurons with the mutations associated with ALS and FTD had more cryptic exons in their UNC13A transcripts, but only when TDP-43 was also lacking.

The other team, led by Dr. Aaron Gitler at Stanford University and Dr. Len Petrucelli at Mayo Clinic, analyzed the gene activity of postmortem neurons collected from patients with FTD or ALS. They identified 66 alternatively-spliced genes in neurons that lacked TDP-43 in the nucleus. UNC13A transcripts showed the highest levels of cryptic exon insertion.

When the team reduced the production of TDP-43 in multiple neuronal cell lines, they found more cryptic exon insertion in the UNC13A transcripts and less UNC13A protein being made. They saw similar results when they analyzed brain tissue samples from patients with FTD and ALS.

The scientists noted that mutations associated with FTD and ALS occurred in the same place on the gene that the cryptic exons were located. In addition, they found that TDP-43 levels had to be low for the mutations to cause an issue with gene splicing.

Taken together, the findings show that TDP-43 is needed to correctly splice the UNC13A gene.

“ALS and FTD patients have long participated in genetic studies looking for changes in genes that might contribute to risk for disease,” explains Dr. Thomas Cheever, program director at NINDS. “Here, we see two independent research teams converging to explain how one of these changes can be a critical factor contributing to an entire class of neurodegenerative diseases, as well as a potential therapeutic target.”