Funded Projects

Lithium belongs to a class of kinase-targeting therapies, including the diabetes medication exenatide and the cancer medication nilotinib, that have demonstrated promise as disease-modifying therapies for Parkinson’s disease (PD). Lithium targets protein kinase B (Akt) and glycogen synthase kinase-3 beta (GSK-3B, a downstream target of Akt) in manners that recapitulate those of exenatide and nilotinib. Also, lithium inhibits inositol monophosphate leading to enhanced autophagy and reduced intracellular levels of alpha-synuclein, which is believed to be a primary mediator of the progressive neurodegeneration in PD and is significantly 78x higher in the plasma of PD patients compared to healthy controls. The transcriptional cofactor B-catenin mediates the transcription of neuronal survival genes implicated in PD such as nuclear receptor related 1 (Nurr1), which is significantly reduced by 61% in PD peripheral blood mononuclear cells (PBMCs). Through its ability to inhibit GSK-3B, lithium can enhance B-catenin-mediated activity and Nurr1 expression. Lithium is also effective in several PD animal models. Lithium may be effective in dosages low enough to be available as an over-the counter (OTC) dietary supplement, which would greatly improve its worldwide accessibility compared to prescription medications. Both clinical trial and epidemiologic data suggest that lithium exposures of even <1mg a day may provide significant disease-modifying effects in neurodegenerative diseases including PD. We propose to assess the effects of 3 lithium dosages (2 OTC dosages and a “low-dose” prescription dosage) for 24 weeks on the above targets measured in blood in a randomized, parallel design, proof of concept clinical trial among 18 PD patients. Changes in plasma alpha-synuclein, PBMC Akt and GSK-3B levels as well as Nurr1 expression will be primary outcome measures. Results will identify the lithium dosage and PD subgroup(s) most appropriate to study in future PD trials.