Study Rationale:
Parkinson’s disease (PD) is characterized by the degeneration of dopamine-producing neurons in the brain. We recently discovered that a protein called FAIM can protect neurons from stress-induced death by preventing or reversing the aggregation of alpha-synuclein, the major pathological hallmark of PD. Furthermore, we found that FAIM-deficient cells accumulate more cytotoxic alpha-synuclein. However, it remains unknown whether FAIM activity is depleted in the cells or tissues of people with PD, and whether FAIM supplementation could slow disease progression.
Hypothesis:
We hypothesize that FAIM inhibits the misfolding of alpha-synuclein and dissolves alpha-synuclein aggregates in cells, and that loss of this aggregate-clearing activity is relevant to the pathophysiology of PD.
Study Design:
Using genome engineering technology, we will generate neurons derived from the cells of people with mutations in SNCA, the gene that encodes alpha-synuclein. Mutations in SNCA cause dopamine-producing neurons to make a form of alpha-synuclein that is prone to aggregation, which leads to cell death. To determine whether — and to what extent — a deficiency in FAIM participates in PD pathology, we will generate neurons that lack FAIM and compare their survival and alpha-synuclein aggregation with that of neurons that contain normal amounts of FAIM. In addition, we will assess whether further increasing the amount of FAIM in these neurons reverses PD pathology.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The results of the current proposal could shed light on the physiological role of FAIM in PD and lay the groundwork for future translational studies, including rationally designed, disease-modifying therapies for combatting the underlying pathogenesis of PD using FAIM activity to prevent or reverse the formation of toxic alpha-synuclein aggregates. Genetically analyzing the FAIM gene in individuals with PD—to assess its function—could potentially improve diagnosis and prognosis.
Next Steps for Development:
If this study is successful, we will screen drugs for their ability to enhance FAIM activity, identify more active FAIM variants, and develop clinically useful combination therapies that couple FAIM’s aggregate-dissolving activity with other therapeutic agents that target alpha-synuclein. We will also establish and verify a system for delivering FAIM to cells using pre-clinical PD models and dopamine-producing neurons derived from people with PD.