Discovery of ALS and dementia mechanism points to new treatment strategy

Almost all cases of amyotrophic lateral sclerosis (ALS) and half of frontotemporal dementia (FTD) cases are linked to dysfunction in the protein TDP-43. New research from two separate teams have now linked the problem with one of the strongest genetic risk factors for the diseases, revealing a possible biomarker and new therapeutic target.

The lack of TDP-43 could sabotage the proper expression of an important neuronal protein called UNC13A. Things could get worse when UNC13A genetic variants were present, increasing the risk to more severe ALS and FTD. Two research teams, one led by Stanford University and Mayo Clinic and the other by University College London (UCL) and the National Institutes of Health (NIH), described those same discoveries in studies published in Nature.

The researchers now view restoring normal UNC13A production as a possible new strategy for therapies against ALS and FTD. It’s worth noting that several scientists from Maze Therapeutics, a Fierce Biotech 2019 Fierce 15 winner, participated in the Stanford-Mayo study. The California biotech is focused on drugs targeting genetic modifiers behind ALS and other diseases.

TDP-43 plays a key role in RNA processing by ensuring mRNA is properly made before protein synthesis. The researchers set out to identify genes that aren’t normally processed without TDP-43 and may give rise to ALS and FTD.

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Besides STMN2 and POLDIP3—both of which have been extensively validated as targets by TDP-43—UNC13A returned as one of the genes with most altered RNA activities without TDP-43. Depleting TDP-43 led to reduced UNC13A mRNA and protein. The teams got the same findings from both postmortem brain samples from ALS and FTD patients and from neuronal cells developed from induced pluripotent stem cells.

Because UNC13A protein resides in most synapses between neurons and has an essential role in facilitating neuron communication, loss of this critical protein as a result of TDP-43 dysfunction could be a major mechanism behind the motor neurodegeneration in ALS and FTD, the researchers suggested.

In addition to an influence from TDP-43, some common variants to the UNC13A gene have been linked to increased risk and severity of ALS and FTD. But the exact disease-causing mechanism was unclear, especially as they are also present in a large population of healthy people.

The risk-associated UNC13A variants could make the gene more vulnerable to TDP-43 deletion, the researchers found, as the UNC13A mRNA was more likely to become abnormal. The variants seem to act “as a kind of Achilles’ heel, not causing problems until TDP-43 becomes dysfunctional,” the Stanford-Mayo scientists wrote in their study.

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Scientists have dedicated a lot of work to pinpointing the generic factors behind ALS. Mutations in the SOD1 gene have been linked to some cases of familial ALS. A group of scientists at Mayo Clinic and the University of Pennsylvania faulted a mutation in the C9orf72 gene.

Previous research from Harvard University identified STMN2’s relationship with TDP-43—much similar to that between UNC13A and TDP-43 as uncovered in the current two studies—as a possible mRNA target.

Because UNC13A is more highly expressed in the brain than in the spinal cord, the Stanford-Mayo team hypothesized “STMN2 could have a key role in lower motor neurons in the spinal cord, whereas UNC13A could have a key role in the brain,” suggesting a combination of effects might be at play in ALS and FTD.

Based on the findings, scientists at UCL hope to “carry out trials over the coming years” for a treatment that stops UNC13A mRNAs from being corrupted in patients, Pietro Fratta, Ph.D., the UCL-NIH study’s co-corresponding author, said in a statement.