Fighting ALS, dementia and more by trapping toxic brain proteins

A pathological form of the protein TDP-43 that’s prone to clumping up in the brain has been implicated in 97% of amyotrophic lateral sclerosis (ALS) diagnoses. It’s also to blame for some cases of Alzheimer’s, chronic traumatic encephalopathy and frontotemporal dementia. But what if TDP-43 could be harnessed in a way that prevents it from forming those toxic clumps?

That’s the strategy researchers at the University of Pittsburgh are pursuing. They’ve developed an “oligonucleotide,” a short strand of RNA, that can prevent TDP-43 from building up in neurons. They described the method in the journal Neuron.

The research team started by reproducing toxic TDP-43 in a dish, using light pulses to coax the protein to form harmful balls. They noticed that the technique only worked when the protein lacked “RNA binding partners,” which normally fuse together to prevent clumping. So they created oligonucleotides that mimic RNA binding partners.

“We call them 'bait-oligonucleotides,’” said senior author Christopher Donnelly, Ph.D., assistant professor of neurobiology and scientific director of the LiveLikeLou Center for ALS Research at the University of Pittsburgh Brain Institute, in a statement. “If you're fishing, you're trying to use bait to trap the fish. In our case, we're leaving the bait there for the extra protein to keep it from clumping together.”

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Most efforts to address errant TDP-43 to date have targeted the gene that produces the protein. In January, for example, Harvard researchers announced they discovered a connection between the TDP-43 gene and another gene, Stathmin2 (STMN2). They found that STMN2 deteriorates in lockstep with TDP-43, which hampers the repair of damaged neurons.

Last year, researchers at the University of Pennsylvania demonstrated that PARP inhibitors, which are currently on the market to treat some cancers with BRCA mutations, can prevent the abnormal clumping of TDP-43 by interfering with its ability to bind with a molecule called poly(ADP-ribose).

The University of Pittsburgh researchers believe that targeting the aggregation of TDP-43 rather than the gene directly could result in a therapy that’s broadly applicable to many brain diseases.

"The problem is the vast majority of patients with neurodegenerative disorders do not have specific mutations," Donnelly said. "Instead of targeting the gene that causes disease in a subset of patients, we're targeting the proteins that clump in nearly all of them.”