A new molecular pathway shared by the two discovered neurodegenerative diseases

Overview: Mislocalization of the TDP-43 protein alters the genetic indication of UNC13A. The findings provide potential new therapeutic targets for the treatment of ALS and frontotemporal dementia.

sauce: NIH (National Institutes of Health)

Researchers from two independent research teams have found that mislocalization of a protein known as TDP-43 alters the genetic directives of UNC13A, amyotrophic lateral sclerosis (ALS), frontotemporal dementia. It has been found to provide therapeutic targets that may also affect the treatment of type dementia (FTD), and other forms of dementia.

ALS and FTD are two neurodegenerative diseases, often due to the mislocalization of TDP-43, rather than being predominantly located in the nucleus of the cell where the gene is activated. Form an aggregate on the outside of the nucleus.

Rare mutations in the TDP-43 gene are known to cause ALS, but almost all cases of ALS show mislocalization of TDP-43.

The study was published in Nature..

“Patients with ALS and FTD have long participated in genetic research looking for genetic changes that may contribute to the risk of disease,” said Program Director, National Institute for Neurological Disorders and Stroke (NINDS). Dr. Thomas Cheever said.

“Here, two independent research teams come together to explain that one of these changes is an important factor contributing to the overall class of neurodegenerative diseases and may be a potential therapeutic target. doing.”

One study was Michael Ward, MD, Ph.D., a NINDS scientist at the National Institutes of Health. And Pietro Fratta, Ph.D., Professor of University College London Queen Square Motor Neuron Disease. This is a joint research by our laboratory. The UK Center first examined neurons grown in the laboratory derived from human-induced pluripotent stem cells (iPSCs), often stem cells made from patient tissue samples such as skin and blood. rice field.

Using powerful genetic tools, researchers have created neurons that produce far less TDP-43 protein than normal. This resulted in the emergence of an aberrant mRNA sequence inserted into an instruction used to produce several other proteins. These abnormally inserted sequences, called mysterious exons, can result in defective proteins or even prevent them from being made altogether.

The UNC13A gene is important for maintaining 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 containing latent exons when TDP-43 is reduced, and latent exons were also found in neurons taken from postmortem tissue of ALS and FTD patients. These findings directly link the established risk factors for ALS and FTD to the loss of TDP-43.

“With the discovery of a new molecular biology that builds on years of genetic research identifying that UNC13A is involved in motor neuron disease and FTD, and confirms that genes are the absolute basis of the disease process. “Supported,” said Dr. Ward.

At the same time, Dr. Aaron Gitler, a professor at Stanford University in Stanford, California, and his lab were with a team led by Dr. Ren Petrcelli, a professor at the May York Clinic in Jacksonville, Florida. We are also looking at the effects caused by the loss of TDP-43 associated with FTD and ALS.

They first analyzed existing datasets in which postmortem neurons in patients with FTD or ALS were classified based on whether their nuclei contained TDP-43. Comparing genes between neurons with and without TDP-43, UNC13A reappeared as a neuron significantly affected by the loss of TDP-43.

Knocking down TDP-43 in otherwise healthy cells introduces a potential exon into the UNC13A gene, suggesting a direct effect on the gene itself. They also show that the genetic code differences between FTD and ALS-related UNC13A mutants occur where the mysterious exons are located. Mislocalization of TDP-43 is also known to cause mysterious exon splicing to another gene that is depleted in motor neurons and encodes the protein stathmin 2, which is involved in neurodegeneration.

Both studies suggest that developing means to increase UNC13A or stathmin 2 levels may be effective in preventing neuronal death in these tragic disorders.

Mislocalization of TDP-43 has been found in other degenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy (CTE), marginal predominance, age-related TDP-43 encephalopathy (LATE), and inclusion myopathy. It may be possible to extend the findings to these diseases. Conditions too.

Funds: The research is partially supported by NINDS’s on-campus research program and grants from NINDS (NS097263, NS097273, NS123743, NS084974, NS104437, NS120992, and NS113636) and the National Institute on Aging (AG071326, AG06267, and AG006786). I did.

About this neurodegenerative research news

author: Nina Lichtenberg
sauce: NIH (National Institutes of Health)
contact address: Nina Lichtenberg – NIH
image: The image is in the public domain

Independent research: Closed access.
“The loss of TDP-43 and SNP at ALS risk cause false splicing and depletion of UNC13A.According to Thomas Cheever et al. Nature

Overview

See also

Loss of TDP-43 and SNP at ALS risk cause false splicing and depletion of UNC13A

Variant of UNC13AAn important gene for synaptic function increases the risk of amyotrophic lateral sclerosis and frontotemporal dementia. It is two related neurodegenerative diseases defined by the mislocalization of the RNA-binding protein TDP-43.

Here we show that depletion of TDP-43 induces a strong inclusion of mysterious exxons. UNC13ANonsense mutation-dependent decay and loss of UNC13A protein.

Two common introns UNC13A Polymorphisms that are strongly associated with the risk of amyotrophic lateral sclerosis and frontotemporal dementia overlap with the TDP-43 binding site. These polymorphisms enhance the inclusion of mysterious exxons in both cultured cells and in the brain and spinal cord of patients with these conditions.

Our findings demonstrating a genetic link between loss of nuclear TDP-43 function and disease UNC13A Mutants exacerbate the effects of reduced TDP-43 function.

They also provide a promising therapeutic target for TDP-43 proteinopathy.