Parkinson’s disease (PD) is a neurodegenerative movement disorder. It is characterised by the loss of dopaminergic neurons in the substantia nigra and the formation of protein aggregates containing alpha synuclein.
Currently, there is no cure for PD. While drugs are able to mitigate the symptoms, they do not actually modify the course of the disease. However, a recent study, published in Nature, developed a machine learning-based workflow which has uncovered new therapeutics for PD.
A Parkinson’s-like motor dysfunction
Recent research has identified that the dysfunction of branched chain amino acid transferase 1 (BCAT1) is linked to PD. BCAT1 expression is decreased in the substantia nigra of PD patients. Furthermore, knockdown of neuronal bcat-1 in Caenorhabditis elegans causes abnormal spasm-like curling behaviour with age. This PD-like motor dysfunction in C.elegans serves as a new model for PD motor symptoms.
Using a machine-learning algorithm, the researchers developed a highly versatile workflow able to quantify C.elegans behavioural phenotypes, such as this PD-like curling behaviour.
First, they completed a high-throughput analysis of 17,000 worms, objectively measuring this spasm-like movement. Then, they completed a proof-of-concept screen of 50 FDA approved drugs, to identify drugs which ameliorated this PD-like motor dysfunction. The drugs tested had a wide range of clinical indications and targets/mechanisms of action. Drugs with non-neurological indications were also included in an attempt to discover new therapies.
The study concluded that Enasidenib, Ethosuximide, Metformin and Nitisinone are promising candidates for repurposing to PD. While only Ethosuximide is currently prescribed for a neurological disease, the known targets/activities of the four candidates seem to converge on similar cellular pathways related to metabolism.
This data suggests that drugs with metabolic targets may represent a potential new class of therapies for PD and opens the door for the testing and development of new therapeutics.
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