Inhibitors to reduce the amount of TDP43 and treat ALS

Valle Palomo

CISC, Spain

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder classified as a rare disease that involves motor neuron death and yields in muscular paralysis and death. Sporadic and familial ALS patients contain cytosolic protein aggregates of hyper phosphorylated Transactive Response DNA Binding Protein 43 (TDP-43). TDP-43 is a nuclear protein that under pathological conditions translocates to the cytosol, undergoes phosphorylation and forms insoluble aggregates, producing not only toxicity but also decreasing its physiological levels in the cell nucleus. Casein Kinase 1 (CK1) and Cell Division Cycle 7 (CDC7) are kinases that phosphorylate TDP43 and due to this role, they are implicated in ALS pathology.

The assets of the project are based on two families of CK1 and CDC7 inhibitors able to modulate pathological TDP-43. The research team has proven, in human cellular models and in vivo experiments, that these small molecules able to inhibit the activity of these kinases are able not only to reduce the amount of phosphorylated TDP-43, but also to increase the levels of TDP-43 in the nucleus, restoring its normal physiological role, and protecting motor neurons. With this proposal, the project aims to validate protein kinase inhibitors as novel therapeutics for ALS.