Those with ALS often have a string of repeated DNA codes within their brain cells which carry thousands of copies within the C9orf72 gene. Investigating what triggers these repeated sequences to eventually produce toxic proteins associated with ALS, frontotemporal dementia, and other neurodegenerative disease in patients carrying C9orf72 mutations findings showed neuronal excitation and stress triggered protein production in cells, and revealed targeting this stress response with trazodone can reduce toxic protein production.
In a collaborative study understanding what triggers toxic protein production helped the team to focus on drugs that could block them in laboratory testing: colleagues tested what causes repeat DNA sequences within C9orf72 to activate and produce toxic proteins; suspecting stressors may be a trigger a number of agents that cause neurons to turn on stress responses were tested, many of which initiated production of toxic proteins.
Neuronal over excitation similar to what happens during a seizure was also shown to trigger toxic protein production; cellular stress and over excitation eventually converge into integrated stress responses, which once activated are difficult to stop production of these toxic proteins. Focussing on the over arching cellular mechanism provided hints to specific methods that may block neuron damaging responses.
Trazodone which is already approved for the treatment of depression is known to act on parts of integrated stress response and was chosen to be tested in models of the disease; the team found that trazodone could block production of toxic proteins in a cellular model that contained the repeat C9orf72 mutations. The work is being expanded to screen for other molecules which may work better than trazodone.
This work also demonstrated importance and benefits of working in collaboration which allowed for speeding up the research processes of moving from identification of the pathogenic stress to investigating potentially useful drugs. ALS is a complex heterogenous disease which requires a collaborative approach with each lab contributing their expertise to fill in gaps from the other to put together the complex puzzle in a systematic and efficient manner.
