Trazodone, which is approved for the treatment of depression, showed promise in mice models in a study that examined how to block the protein that is considered responsible for inherited amyotrophic lateral sclerosis (ALS), according to a new report.
Investigators from Thomas Jefferson University in Philadelphia analyzed whether different cellular stressors promote expansions of C9orf72, the most common genetic cause of ALS and frontotemporal dementia (FTD). Repeated DNA code in the brain cells carry copies of C9orf72, which then eventually produces the toxic proteins associated with ALS.
Specifically, the investigators tested what caused the sequences to toxify and produce the protein and suspected various stressors as the trigger. They also tested a number of agents that cause neurons to activate stress responses.
They found that many of these agents initiated production of the toxic protein. The team also demonstrated that neuronal over-excitation, such as what happens during a seizure, also triggered the protein production. These cellular stressors and the over-excitation converge into what the study authors called the integrated stress response.
The team noted that this integrated stress response is difficult to start once it starts to produce the toxic proteins. Further examination of this process also allowed the investigators to test what methods might block the response though.
They tested trazodone, a drug known for its ability to interact with parts of the integrated stress response. They found that trazodone blocked production of the toxic protein in a cellular model that contains the repeated C9orf72 mutations.
“This is a significant step forward in our collaborative approach,” the study’s co-author Piera Pasinelli, PhD, said in a press release
. “Working together allowed us to speed up the research process getting from the identification of the ‘pathogenic stress’ to testing a potentially useful drug. ALS is a complex and heterogenous disease that needs this collaborative approach, with each lab contributing its own expertise, to fill the gaps and to put together this complex puzzle in a systematic and efficient way.”
The next step for the investigators is to expand their research and screen for other molecules that might show an improved response than trazodone did, such as the FDA-approved dibenzoylmethane. Both of these drugs cross the blood-brain barrier, have little toxicity, have been previously used for depression treatment, and have been repurposed as Alzheimer’s drugs and treatment for other diseases.
The team believes that their work “provides early findings for new therapeutic avenues to ameliorate toxic polypeptide production caused by the non-AUG-dependent translation of nucleotide repeat expansions (NREs), which is a proposed pathogenic mechanism identified for a number of neurological or neuromuscular disorders,” they wrote.
“Understanding what triggers toxic proteins production helped us hone in on drugs that could block them in laboratory tests,” added co-senior author Aaron Haeusler, PhD.
The paper, titled “Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress
,” was published in the journal EMBO Molecular Medicine